Legend Biotech Corporation (LEGN) Earnings Call Transcript & Summary

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 to the Legend's first Research and Development Day. Today, you will be hearing from our executive team, highlighting the progress on the select numbers of [indiscernible] programs. After the presentations, we would like to hear from you and take your questions. I'll just 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 Investors section of legendbiotech.com. Please note that today's presentation includes forward-looking statements. We encourage you to review this 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. And during the next hour, Dr. Lida Pacaud, VP of Clinical Development; and Steve Gavel, 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 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 in the room, and also welcome everyone online as well. So it's a pleasure for me to welcome you to the Legend Biotech's first R&D Day. As some of you may know, Legend Biotech had the opportunity to ring the opening bell at NASDAQ a few weeks ago. And as I rang the bell as reflecting what and also we have accomplished since the founding in 2014. In 2016, the first in-human study called LEGEND-2 was initiated. And 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 United States. Just over 3 years later, we're here awaiting FDA approval with a PDUFA date of November 29. 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 the 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 Gavel, Vice President of Commercial Development, will share updates related to our CARTITUDE clinical programs, and also updates on the commercialization of cilta-cel as we edge closer to that PDUFA date of November 29. Lida is an experienced clinician, who joined us from Novartis, where she served as Global Clinical Program Lead and also Executive Medical Director in the Cell & 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 long-term 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 VELCADE marketing, strategy and execution at Takeda Oncology and held multiple sales, marketing and the market access leadership positions in companies including Johnson & Johnson, Immunex, Syntex and IMS Health. Dr. Frank Fan, our Chief Scientific Officer and the inventor of cilta-cel, is a transplant surgeon and an expert in the field of human B-cell tolerance. Before joining Legend, Frank helped identify the underlying mechanism of antibody generation in single B cells and developed one of the first anti-HIV-1 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. 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 the 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 cilta-cel has demonstrated better efficacy, while it's coming from this dual binder design, since T cells are collected from patients in the autologous CAR-T program. I hope you'll 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 antibody engineering effort. And 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, allogenic CAR-T, TCRT and NK. We don't pretend to know which technology will win the race of allogeneic cell therapy. And that's why we're investing in diverse allogeneic platforms, including non-gene-editing alpha/beta T-cells, gamma/delta T-cells and Natural Killer cells. Our development strategy will be driven by science and only science. And we do believe that multiple arming strategies will be necessary to overcome challenges to use T cells to treat solid tumors. So finally, I would like to close my introduction with why we do this here at Legend Biotech. You may remember that LEGEND-2, the first in-human study, is what catapulted Legend and helped us become who we are today. I'd like to share a story of patient #6 from LEGEND-2 study. Patient #6 is a 61-year gentleman, who was diagnosed with multiple myeloma in April 2014. He had the type of lambda light chain myeloma, with 5 prior lines of therapy, including Revlimid. This patient was dosed with cilta-cel in June 2016 with a total dose of 0.5 milli CAR-positive cells per kilogram body weight. And you can see from this photo on the slide taken on the day of infusion on day 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 additional maintenance treatment since then. As of last follow-up on May 26, 2021, patient #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. And this patient is due for the next follow-up in November, and we have not heard any progression as of today. Multi 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 #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 #6 in front of the second affiliate Hospital of [ Xian Carlton University Medical School ], 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 cell. With the story of #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 targeted therapy, cilta-cel.

Thanks, Ying Huang. Welcome, everyone. So my name is Lida Great. Thanks, Ying Huang, and welcome, everyone. So my name is Lida Pacaud. I'm Clinical Lead at Legend for BCMA program as well as early-stage pipelines. So today, I would like to give updates on cilta-cel clinical development program. I will start by reviewing new data of our CARTITUDE-1 study, our registration study. I will also review CARTITUDE-2. This is a multi-cohort Phase II study. And lastly, I will cover our Phase III programs as we move cilta-cel in earlier line setting. So this will be 2 Phase III studies, CARTITUDE-4 and CARTITUDE-5. So 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 pretreated multiple myeloma patients. This is overall response rate in this updated analysis at 97.9%, and responses are deep and durable. This is indicated by stringent CRs being 80.4% and also by the 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. So some patients like 1/3 of the patients who had VGPR became CRs. And importantly, CR patients became stringent CRs. So 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 the long-term benefit for the patient, and this is indicated by progression-free survival. So what we see here in these 18 months analysis is that the lower confidence interval indicates that minimum PFS benefit is a 22.8 months. These curves will continue to mature and we will continue to report data in major clinical conferences. With that, we are very excited to provide such a potentially effective therapy to heavily pretreated multiple myeloma patients. Response rates seen here is exceptional in oncology and in our careers, and we are pleased to share this data with you. So now I would like to invite Steve to give you a commercial perspective on this data.

Thank you. Am I turned on? We good? Okay, good. Well, good morning, everybody. What's really a treat for me, during the IPO process, I've had -- we did not have the opportunity to meet face-to-face with many folks in this room. And when you IPO virtually, that's always an interesting experience. So it's always now very, very helpful for me and it's a personal type of connection to personally welcome you all, and also thank you for your continued interest in Legend. So obviously, the clinical data speaks for itself. And what I'd like to do with my piece of this presentation is give you a commercial perspective of what that means in the geographies that we will be launching into. So the take-home message as it relates to our label assumptions are as follows. We are assuming that in all regions that we launch into that we will mirror the same indication statement as our competitor. So just to remind folks, in the United States, we are assuming that we will have a fifth line plus label. What you see up here on the parentheses or just below that in sub-bullet, I should say, around 12,000. What 12,000 represents, this is the eligible patient population in the United States that will meet this label requirement. It does not necessarily mean 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. But I just wanted to pull that out, and 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, this is in keeping what you saw earlier with eye T-cell, representing about a 6,000 or so patient population that would meet the eligibility criteria. And then in Japan, also a fourth line plus indication, again, a population of about 4,000. Now 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. So 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 we established, a bit of an interest in the private pay sector to look at potentially expanding the use beyond fifth line. So we're keeping our close eye on this because, obviously, with the eye T-cell just launch just occurring and there's really has been really relatively speaking kind of 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 notes -- statistical notes, that represents about 10,000 incremental patients in the fourth line setting. So obviously, from a promotional end, we would not be able to promote to that, obviously. This would be off-label use. But 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. So 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, so how does the co-pro work? What are you doing? What's your partner doing? So what we agreed to now, a couple of years ago, was that within the hospital setting that we will be selling into is where Legend will play. So we have deliberately gone out and actively recruited and trained and hired folks in the industry who have a lot of gene and cell therapy experience as well as multiple myeloma experience. And a lot of these folks obviously have spent a lot of time in hospitals. So we think that we've got a very relationship set up, Legend in the inpatient setting and largely Janssen in the outpatient setting. So let me just end, I guess, on my piece of this as it relates to the initial indication in terms of what we are also hearing in market in terms of how our customers, most importantly, are evaluating these CAR-T drugs. And it's interesting now to watch for me since working on my old program when I was at Celgene and where I am today how that review has changed quite a bit over the last -- now for me, it's about 5 years in total -- 5.5 years. So as we all know, it all starts with the data, right? The clinical data, safety and efficacy data of all these drugs without question. And I think what you're hearing from Lida is from that perspective, we have quite a hot product on our hands right now. So we're feeling very comfortable from our clinical profile for sure. But what we also know and a really good example of this are some of the prior CD19 launches is that just because you have a hot, cool technology, doesn't necessarily that are going to be commercial successes, right? And one of the things that has been playing in market to us loud and clear, and this is an extension of our safety profile, is how interested the market is in using cilta-cel and bridging patients into that hospital outpatient setting. And 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 the CRS of about 7 days, that allows hospitals a lot of operational flexibility in terms of what to do with that patient and where to potentially administer this product. And that's more and more important for sites, especially as you're launching into large patient populations like multiple myeloma because when you do the math, and I've done it now a couple of different times, in the United States, in particular, and that's true globally, there are just not enough beds to treat all of these multiple myeloma patients and continue to do all the other work that you're involved in these hospitals, whether it be in transplant or in the clinical trial setting. So this is one of these operational aspects of this product that I truly did not appreciate until we got going with it. But this is something that is clearly resonating in market as an exciting also added feature of this program. And then finally, because of this combination of obviously, safety and efficacy and operational flexibility, at the end of the day, it enables these hospitals and providers to treat more patients. And one of my concerns as this product was picking up speed clinically because of the great work our clinical teams have been doing that and we hear it 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. And what I was getting worried about is the operational mechanism within these countries if they could pull it through. So the fact that, like I said, I think the CRS aspect is the enabler to actually treat potentially more patients than the outpatient setting. So I'll leave you with that. And I'm sure it during the Q&A, we could get further into that. So I'll turn it back to Lida.

Thank you, Steve. So next trial, I would like to review our Phase II CARTITUDE-2 study. So this is a multi-cohort study, which evaluates various multiple myeloma settings. We anticipate to enroll approximately 160 patients. And this -- so you see, we have 6 cohorts right now. And in each cohort, there's 20 patients or more. We do -- this trial was designed and these cohorts are designed to support or inform our Phase III programs or they are designed to generate data, which will be practice-informing. So I will start by reviewing Cohort C. So I will start with later line setting. So Cohort C is a patient who are exposed to PI, IMiD, anti-CD38 agents, but also exposed to BCMA-targeting therapy, except cell therapy. So this is basically cohort patients who had prior BCMA, ADC or bispecifics. Next court is Cohort A. So this is, again, relapsed refractory setting, but patients with prior 1 to 3 lines of therapy, earlier than CARTITUDE-1. And we have Phase III trial also ongoing in this population, which I will come in a moment. So we have disclosed this Cohort A 20 patient data, and I will share that with you in a moment. So rest of the cohorts are also investigating cilta-cel in earlier line settings. So if we go to Cohort B, these are patients who are early relapses after frontline therapy, patients 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 patients. And last cohort is also newly diagnosed patients with standard risk, and this last Cohort F will investigate patients after induction of DVRd or similar triplet regimens. Cilta-cel will be given as after induction as a consolidation. So 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. So we see 95% of patients have overall response, and the CR was seen in 75% of the patients. So this data has a median of 5.8 months follow-up. And as I have mentioned from CARTITUDE-1, we have learned that responses are going deeper over time. So we will look forward also to update this study in the future. I also would like to highlight safety profile in this earlier line setting. So we see a similar safety profile to CARTITUDE-1 in terms of targeted adverse events or some other events, even numerically better. So this is very encouraging as well. So we see overall 85% of patients with CRS, but vast majority are low grades. And in this subset, we did not see Grade 3 and 4 neurotoxicity, which also includes we did not see a movement in neurocognitive type of neurotoxicity. And start of CRS and neurotoxicity, I think to the point what Steve was mentioning. So we see like 7, 8 day, 7 for CRS and 8-day median start for cilta-cel. Now I would like to introduce CARTITUDE-4 Phase III study. So this is same patient population with prior 1 to 3 lines of therapy and refractory to lenalidomide. Patient should have had exposed to PI and IMiDs. And I would like to highlight daratumumab exposure was not required in this trial. So it means this trial will cover both populations with or without prior daratumumab. And I guess, Steve will come to this point as well because we want to highlight in the context of we know there is CARMA study, which is ongoing, which is different. So CARMA study has prior 2 to 4 lines. So this trial is 1 line earlier, and CARMA trial, as we know, requires daratumumab exposure, but here, both populations will be covered. This is trial Schema. So trial is -- we will enroll approximately 400 patients, and we will give a control arm, PVD or DPd standard of care regimen. PVd stands for Pomalidomide Velcade Dex and DPd is the Darzalex Pomalidomide Dex. And patients are treated in control arm until disease progression. In cilta-cel arm, there will be bridging therapy, 1 cycle or more, so maybe 2 if needed. And after this bridging therapy with the same regimen, patients will undergo cilta-cel infusion, lymphodepletion and cilta-cel infusion. After cilta-cel infusion, there is no treatment. So there is observation treatment-free period for patients. This trial has opened in June last year, and we are very excited because we have seen very high interest from investigators in terms of recruitment, even better than we have forecasted. And this trial, it's clear, was very priority for Janssen and Legend. So we hope to report on the progress of this trial very soon. And also to put this trial in a context. So just to highlight what is available standard of care right now and what benefits this can provide to this population. So we see, as highlighted here, 9, 10 months is a benefit in lenalidomide refractory patients specifically, which are studied in this studying.

Do 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. And thanks for the setup, Lida. So I won't go into the trial design. But 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. So with this indication, fundamentally, this will be the first time that this program cilta-cel will now jump in front of ide-cel. So that's one of the key points to the slide. The second piece, and jumping ahead, as you can see further down the slide, our competitive assumption, 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. So that's the timeframe we're looking at. But again, with this indication, so we look forward in front to the 1 to 3 to prior. But the interesting aspect, and the reason why I love the trial design so much is the fact that the lack of requirement for daratumumab. And as you could see in the sub bullet, it's probably hard to see here for the folks in the room. But based upon the data that we've been analyzing, about 80% of all patients in the second line setting do not -- or have not been exposed to daratumumab. So you can see the implications here. So most importantly, for our patients and their providers who want to use CAR-T upfront for patients who have not seen dara, which is an overwhelming majority of them, this now -- this study now enables them to get involved in CAR-T therapy early. I can't say that loud enough, right? That's probably the most important takeaway from the slide. And again, if you go further down to 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. So it's an extremely exciting study. I'm really excited about it for our patients because it's going to really open up, where I believe, our competitor went there, but you're going to still have an issue with the early indication of the daratumamab requirement. Now you move forward with cilta-cel earlier without this Dara requirement. So I'll pass it back to you.

Okay. Thanks. So last trial is CARTITUDE-5. So this is a trial in newly diagnosed multiple myeloma. So to our knowledge, first newly diagnosed clinical trial for CAR-T therapy in myeloma. So this trial will enroll patients who are not candidate, so not considered for stem cells transplantation. So there is 2 categories of the patients. So one is patients who are not candidates because of age or comorbidity organ function, and this is based on local institutional recommendations. So this is, as you can imagine, international trial and definition of transplant non-eligibility various among countries. So one population will be transplant not eligible because of clinical conditions or age. And then there is a population of patients who are deferring autologous time cell transplant as a first-line therapy. So this population emerged in last couple of years. And these are patients -- so there was actually the IMF study, so clinical study, which have shown that survival benefit is same if patients received transplant immediately in newly diagnosed setting or later in a treatment course of disease. So that's led to investigate this population differing transplant by physicians and patient choice. That was also investigated actually in 3 other Phase III trials of multiple myeloma, so non-CAR-T trials. So this is now becoming -- in the last couple of like 5 or so years, becoming a population, which is treated together with transplant not eligible patients. And -- so yes -- so basically, this trial will cover these patients as well. And yes, I wanted to highlight also 2 references. So I looked through some references. And like half of the patients right now are differing transplant, not undergoing it in first-line setting based on literature. So trial Schema is shown here. So this will be a 650 patients randomized clinical trial. Patients in investigation -- in control arm will undergo via the regimen, Velcade, Revlimid, Dex. So as you can notice, all patients will have 6 cycles of induction, and after randomization, in both treatments are there are 2 cycles of this regimen. So this basically makes that in both treatment arms, total, so equal number of cycles are given to the patient as induction. And in control arm, there will be RD maintenance or Revlimid, Dex maintenance. And in investigational arm, 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 more than 100 locations worldwide. And also to put again this trial in the context and patient population, we try to address here. So this is data from some literature, which shows that median PFS in this patient population with current standard of care is around 36 to 40 months.

Very good. Thank you, Lida. Again, just to reiterate, so now 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. Because I think our providers are seeing the future, and they obviously see that this potential asset of ours has a good place in the future in the upfront patient population. So when you take a look, again, back here at some of our assumptions, if you look at some of the newly diagnosed patients, 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 then in Japan, a 16,000 -- or 1,600 patients. One of the things -- I guess, the only point I really want to make in this study, the economics really start to change here. And the economics that I'm referring to is demonstrating success in the 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. So one of the key things that we are starting to model now is to model out what success would look like, not only obviously clinically for our patients, but also economically for all of us. As we are successful in earlier lines, you'll see a much larger economic input -- or impact on society, and we're very, very excited by that.

Okay. Great. So thank you, Lida and Steve, about the introduction on of CARTITUDE program. So as you can see from this slide, we have a very comprehensive clinical program, including the ongoing CARTITUDE-1, which is a registration of 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 1 in China, which will serve as a basis for BLA in China. Besides that, we all have an ongoing Phase II trial called CARTITUDE-2 that is evaluating cilta-cel in various settings, including frontline. In the Phase III, CARTITUDE-4 examines cilta-cel in patients with 1 to 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. So 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 relapsed and refractory multiple myeloma with 80% stringent CR rate. And most importantly, I want to emphasize that in the clinic, we have seen that those CR rates achieved our durable CR. And the CR rates increased over a 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 an 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 metical myeloma.

And now we will take a 10 minutes coffee break, and we will resume at 10:50 a.m. [Break]

Okay. Welcome back. And I now have the pleasure of introducing you to the man behind cilta-cel, who leads also our discovery research at Legend Biotech. So welcome, Dr. Frank Fan. Frank, you can take over.

Hi. Thank you. Dear investors and friends, thank you for your continued support to our company. I'm the CFO and Co-founder of Legend Biotech. I'm an implied immunologist and a long-term believer of cell and gene therapy. During 20 years of my academic career, I made some scientific breakthroughs in transplantation immunology rather impacted clinical practice. I returned to China in 2014. And as supported by GenScript, I founded Legend. I'm happy to [indiscernible] 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 2015, I strived to keep a robust R&D culture, added great passion, renovation and cooperation of the core spirits. When looking back to what we have achieved in the past 7 years, I feel it was R&D culture letting the team to bring true miracle to the field. We already set up an example for a start-up biotech company that 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 3 parts of content. In the first part, I will brief you about our core technologies and the capabilities. Then I will introduce you 3 solid cancer programs, which are our current R&D focus. Then 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 complication. We often started R&D activities for a promising target years before it becomes popular. For example, BCMA and CAR-NK too is example. We have developed many technologies to help us efficiently obtain large amounts of protein end of the lease and identify, optimized most promising lease at a preclinical stage. We also own and apply our high-value IP, for example, the multi-specific CAR platform to enhance our product design. We also heavily invested in developing advanced allogeneic CAR-T platforms, which can simplify CMC and lower the cost of the goods with enhanced safety and improved homogeneity. Legend's non-genome editing allogeneic CAR-T platforms do not rely on any genome editing approach. We also have Legend's unique CAR-NK and armored gamma delta T CAR platforms in our development. We have put enormous efforts into developing CAR-Ts to treat high market value cancers, such as gastric cancer, pancreatic cancers, HTC, non-small cell lung cancer and small cell lung cancer and other indications. Because I have limited time today, I want to be able to report to you our Gamma delta T or, our TCR-T platforms. I also don't have enough time to cover all our pipeline products, for example, the CD19, 20, 22 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 has been able to analyze either internal data or public data set to support our pipeline development. Sometimes, we use our NGS platform for target discovery and the validation in a single cell level, such as target expression on tumor cells, on target of tumor risk analysis or normal tissues. When studying tumor microenvironment, we'll be able to find a repressive cell type [indiscernible], guiding the design of our pharma strategy. We, however, done in-depth analysis of clinical samples as well to characterize post-infusion [indiscernible], gene expression and a dynamical change of CAR-T cells. We have multiple in-house antibody development platforms, including candidate VHH single-domain antibodies, multi-epitope antibodies and fully human antibodies. We usually will rely on multiple criteria for screening out the top end of the needs we want to proceed. Llama produces highly diverse antibodies, including a unique class of VHH single-domain antibodies that can have high edited binding potency compared to that of conventional antibodies, which are composed of heavy and light chain domain. These smaller single-domain VHH antibodies are also able to access antigenic sites that are close to the submembrane, which may not be physically accessible to larger conventional antibodies. While our technology has the potential to construct multi-epitope antibodies targeting the same antigen or to enable designing multi-antigen specific CAR construct such as tri-specific CAR products, targeting CD19, CD20 and CD22 at the same time. As you know, one of the latest or current R&D focus is to conquering solid cancers. There are many challenges for our T-cells to overcome in fighting these solid cancers. We took barriers and the best regulated vasculature inside large cancer regions, blocked CAR-T cells, trafficking and infiltration. [indiscernible] tumor microenvironment, including soluble and accelerate suppressive factors plus unfavorable metabolism in tumor, all urge on 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 obviously do our best at each single step in developing a pipeline product. We never cut in [indiscernible]. And usually, when we kick off developing a new product, we start with the research projects from the preparation of target antigen to optimization of antibody immunization regimens. By these step-by-step in-house efforts, we've been able to obtain large amounts of high-quality antibody leads. We polish our product by not only pursuing high specificity and affinity, but also optimizing individual CAR designs by looking for ideal Linker, white Hinge and a robust transmembrane domain. Legend R&D team also proactively combine our complementary suites of technologies at the early developmental stage. We have invented numerous arming strategies and have fired many patent families to enrich our self IP toolbox. For each individual pipeline program, we will be able to screen out the most appropriate arming strategy that can energize the pipeline CAR-T cells while they fight with their corresponding target cancer. We will try to claim any of our armored CAR-T product as so-called the first generation or fifth generation CAR-T. We care more about what our design can really help on CAR-T cells in a very challenging mission. In some cases, we enable our CAR-T cells to transform negative signal to a robust positive signal that could motivate themselves. Some of our invention guided our CAR-T cells to identify their specific cancer signals that facilitate the assembly of a median armor molecule like a self-boosting mechanism, offering our CAR-T cells with powerful tools on the battlefront frontline, but 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 paths towards desired phenotype. For both of CAR-T cells and our CAR-NK cell platforms, we are making progress and we are accumulating our IP portfolio. With 7 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 one team in executing IND-enabling studies or a mission of technical transfer to manufacture teams. We not only have efficient and a talented discovery team, but also have professional analytic development team, skilled by our market experts, and also have experienced early PD personnel. Our ambition is to keep advancing our knowledge in the area of cell therapy and to develop very competitive products in order to keep Legend leading the field. Although, adopted cell therapies have gained tremendous success in the past decade, solid cancer remains the largest unmet clinical need. Legend Biotech also heavily invests to explore new [indiscernible] 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 autologus 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 most frequently diagnosed cancer worldwide and the second leading cause of cancer-related deaths. Pancreatic cancer has extremely low 5-year survival and the second leading cause of cancer-related deaths in the U.S. Because Claudin 18.2 is a [indiscernible] transmembrane protein with very conservative extracellular domain across niches, developing highly selective high-affinity antibody to Claudin 18.2 is very difficult. With years of efforts, we have successfully developed high-affinity Claudin 18.2 VHH single-domain antibodies that does not cross-react into 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-type junction proteins with 4 transmembrane domains and 2 extracellular groups. In human, Claudin 18 has two variants, 18.1 and 18.2. They share highly similar protein sequence in extracellular loops with only 8 [indiscernible] difference in loop 1. Claudin 18.2 -- 18.1 is selectively expressed on normal lung. Claudin 18.2 is restricted in differentiated short-life cells of stomach epithelium. Therefore, highly selective Claudin 18.2 antibody over 18.1 is specifically extremely critical to assure the safety of the Claudin 18.2 targeting biologics, particularly important for CAR-T cell therapy due to this live cell product could expand 100x or even 1000x in dosed patients, and you don't want any of these cells to go attacking your lung tissues. Claudin -- as was reported, summarized in the left panel in EU population, Claudin 18.2 is detecting 77% primary gastric adenocarcinoma, the fraction of tumor cells expressed in Claudin 18.2 at any staining intensity strongly correlated between primary tumors and the lymphoma metastasis in matching price. Claudin is in the single-domain antibody-based CAR-T platform. 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 [ customary ] domains. The safety profile was featured by its high specificity by extensive characterization, including in rebinding studies human normal tissue profiling by IHC studies. And by comparing with benchmarks, LB 1908 showed superior anti-gastric or anti-pancreatic tumor activating in vitro -- in vivo. And I would like to show some representative data for this program. The VHH binding affinity and specificity of [indiscernible] CAR VHH to human Claudin 18.2 were assessed by 2 independent methods, as the PR and [indiscernible], using [indiscernible] cells. Our human pancreatic cancer cell line transfused to express Claudin 18.2. The C18S CAR VHH [indiscernible] to human Claudin 18.2 as a key value of 17.15 [indiscernible] by SPR. In the cell-based [indiscernible], the Claudin CAR [indiscernible] specifically interactively 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 VSHH and the Claudin 18.2. We also use a real-time live cell imaging called culture assay to study the safety profile for LB1908 CAR-T cells, using a series of primary cells. Here are some representative images. After overnight culture, the significant targeted 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 significantly cytotoxicity in other Claudin 18.2 negative cells, including types of cells from human primary normal loan cells. The acid control, CD19 CAR-T, did not show cytotoxicity across these cells. Claudin 18.2 protein sequences are highly conservative among specious. Human and mouse share identical extracellular loop 1 sequence of Claudin 18.2. Therefore, mouse is a highly relevant model to study the Claudin 18.2 targeted biologic, especially toxicology study. We performed in vivo studies using gastric tumor [indiscernible] models based on a highly immune incompetent NCG mouse screen. Gastric cancer cells were inoculated 2 weeks prior to the CAR-T treatment followed by molecule of tumor size, body weight, status and CAR-T [indiscernible]. As you can see in Figure A, the C18S showed significant tumor control in dose-dependent manner. Tumor 3 can achieve 75% of the 1 million group, and all the 3 million to 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 3 weeks prior to CAR-T treatment. Our product showed significant anti-pancreatic cancer potencies in vivo. All tumors were gone in each mice and the LB1908 expanded efficiently. Before we launched exploratory human trial, we also completed our comprehensive human tissue cross-reactivity analysis of LB1908. Antibody by immunochemistry, using frozen human PMA, consisting of 30 different normal tissue in triplicate from 3 different individuals. Membrane staining of the VHH binder is restricted to gastric mucosa mucosal epithelial cells. These results strongly supported the safety profile of LB1908 across human normal tissues. So early this year, we initiated an investigator-initiated clinical trial in Shanghai East Hospital. Considering about safety, we initially restricted enrolling patients with previously total gastric anatomy and subtotal gastric anatomy. With more safety information collected for on-target of tumor effects, we are now considering modifying our protocol to be able to enroll patients with full stomach. This is a prospective single-arm single-cell and open-label single-dose Phase I study to evaluate the safety, tolerability, PK and antitumor efficacy profile of the LB1908 in subjects with Claudin18.2 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 sales per kg. 3 patients completed the DLT observation, and no dose limiting toxicity DLT have been observed to date. The preliminary efficacy data shows antitumor activities of 1908. Since this study is still in its early stage and only the first dose patients have reached the time point of -- for evaluation at day 180 days to -- for follow-up, so we decided to only brief in the first case for now and deliver full report to be disclosed by PI in future academic meeting. The first subject we dosed is a female patient bearing 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 of sitis 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. Therefore, the investigator performed emergent bilateral thalostomy to relieve the critical conditions. 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 discharge from hospital on day 14 post-infusion. And in the half year of follow-up, about 15% of tumor regressions were mirrored and the patient remain progression-free at day 180. Of the CAR-T infusion, this patient not just experienced the reduction of lesion at roughly 15%, strikingly, her urination resumed and the colostomy catheters on both sides were removed. Before CAR-T infusion, the patient has a large amount of situs that needed abdominal damage. After CAR-T infusion, the situs and pelvic infusion was significantly decreased. And by flow cytometry analysis, we see significant reduction of tumor cells, and a large amount of the CAR-T cells appeared in the situs. In each follow-up time point, 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 lost experienced significant CAR-T expansion. The CAR-T cells were detected from day 2 with peak expansion noted on day 12, reached a level above 250 [indiscernible] 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 [indiscernible] from day 92. Despite a very small dose of LB1908 CAR-T cells being injected to the gastric cancer patients, the degree of CAR-T expansion seems to be not inferior to what we have been observing in liquid cancer CAR-T trials. So to summarize the program, we conclude Claudin 18.2 is a very promising target of gastric cancer and pancreatic cancer. But Claudin 18.2 is also a very challenging target for developing a safe and efficacious CAR-T product because of target effects such as cross reactivity to Claudin 18.1 could be fatal and on target of 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 dosed GC patients. We have already escalated the dose level to 3 million per kg and no DLT will a 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, 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 a U.S. IND in the first half of 2022 are currently ongoing. The second program I'm talking about is [indiscernible] CAR-T targeting GPC3. GPC3 highly expressed in over 76% of HCC, 52% LSCC and 80% in germ cell tumors. This target is specifically expressed in these tumors, but not in paratumor tissue. We developed the Legend anti-HCC CAR-T cells based on a highly selective, higher affinity humanized single cFv with optimized CAR backbone, and Legend's own customer CAR-T armors technology has been applied. This next-generation GPC3 is CAR-T executive, improves expansion and invasion, persistence and excellent curing in nonclinical studies. GPC3 over expressed across a broad spectrum of tumor types with high positive percentage. CAR-T therapy targeting GPC3 will cover large patient population indications, including HCC liver cancer, LSCC, a [indiscernible] cancer, thyroid tumor and germ-cell tumors. The Figure B shows GPC3 staining hepatoblastoma. You can see GPC3 could well distinguish tumor cells and apparent tumor liver cells. The high specificity of GPC3 in tumor cells make it a safe target of 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 major CAR-T cells, called H93, and 2 benchmarks. Using an aggressive [indiscernible] demograph model, our H93 CAR showed superior efficacy at a very low dose where [indiscernible] 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 bond strategy with limited systemic 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. And the TME signal itself is not enough to activate the armor biofunctions. Thus, it will not alter CAR-T specificity to GPC3 positive tumor cells. So the GPC-3 CAR-T may not only resist to TME suppression, but it will have more infiltration into tumor nest, expand well and exhibit a more potent tumor killing activities. This data suggests armoring strategies improve CAR-T in vivo functionality. On the left as it figure armor H93T CAR-T cells showed complete tumor elimination since '19, while NK CAR-T obtained no antitumor efficacy at such a low dose. On the middle figure, selected armoring strategy markedly improved CAR-T expansion potency. The CAR-T cells decreased along with the tumor regression. On the right figure, body weight monitoring, no noted body weight loss or other in vivo toxicities were observed throughout the study. In summary, LB2101 is a novel investigational CAR-T therapy for the treatment of HCC, SCLC and potentially more broader indication. Due to LB2101 shows 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 allergenic platforms. Next, I'm going to introduce a newly disclosed solid tumor program treating small cell lung cancer. The target molecule is DLL-3. DLL-3 is a very promising target for SCLC and other neuroendocrine tumors, highly expressed 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 cases, 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 of patients with extensive stage of SCLC is less than 10 months. Similar to the design of cilta-cel, we developed anti-DDL3 CAR-T cells with a tandem humanized single domain derived binder design, which has high affinity and a specificity against the [indiscernible] 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 the TME resisting element to overcome hostile tumor microenvironment. The armor boost in vivo antitumor efficacy by improved CAR-T cell proliferation resistance to TME inhibition and infiltration in the tumor nest very well. The product is well tolerated in both subcu tumor model and a pulmonary orthotopic tumor model. DLL3 belong to the delta-like family protein in SCLC tumors. DLL3 is homogeneously expressed a high level of cell membrane of tumor. In contrast, it is barely expressed in normal tissues are very restricting in the cytotoxic. As shown in the IHC staining DLL3 specifically overexpressed in SCLC and LCNEC. We have developed a DLL3 targeting autologous CAR-T product with SCLC. The product is armored with a tumor microenvironment resistant element. In preclinical in vitro pharmacology studies, we have again demonstrated that similar to cilta-cel, tandem biparatopic single domain antibody derived CAR-T outperformed monospecific DDL3 CAR-T cells. Furthermore, as compared to the conventional tandem CAR-T, LB2102 , the armored TME resisting CAR-T, has secured persistency, proliferation and a cytokine production in response to repetitive simulation, 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 antitumor 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 improving infiltration into the -- and proliferation 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 a causing autologous histological damages. So the conclusion is that DLL3 is a promising target for SCLC, leveraging a biparatopic tandem, single-domain derived binder and the TME-resistant armor strategy, LB2102 has demonstrated a potent cytotoxicity, improved proliferation, persistence and infiltration and efficient in vivo tumor growth inhibition. We are planning first-in-human study and U.S. IND. In Part 3 of my presentation, I would like to present 2 allogenic, our universal CAR platforms 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 a 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 compete with the leading autologous products. The mainstream allogeneic CAR-T heavily rely on gene editing and knockout strategies to prevent the risk of GvHD. However, multiple gene editing or knockout manipulations always come up with risk of off-target and a potential genotoxicity. Also another important disadvantages is a multistep manufacturer will generate 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 manufacturer efficiencies and a low yield of final drug products. Without any gene editing knockout disruption, we aim to achieve silencing of TCR function while spare CAR-T signal transaction. After 5 years of hard efforts by a big team -- by a dedicated team, we managed to get this idea realized by co-expressing immunomodulatory polypeptides to disrupt the TCR complex. The platform now is supported by a series of a patent families, and I'm very excited that we could have this initially impossible mission accomplished. Developing such a difficult to achieve approach there proteomic regulation of TCR is also driven by [ my hobby ] to pursue all-in-one solution. I love a simple step process that is clean, fast and efficient. Translating to the feature of the product, we can pretty much generate a large amount of allogeneic CAR-T cells by a very straightforward and a similar process to autologous product. Conventional allogeneic products now exceptionally involve multistep gene moleculation, including the CAR transduction and a [ non-gene editing ] or gene knockout. This will generate about 8 to 16 different population in the process that need complicated depletion process and a purification process for final DP. The most dangerous phenotype generated will be the CAR TCR double positive cells, which may cross GvHD after extensive on-target expansion in vivo. So the CAR control and a 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 disrupting element is [ code stress ] 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 of the lentiviral transduction. All donor T cells either successfully transfused or not transfused. This strategy will ensure all CAR positive cells or GvHD disarmed T cells that we need and a modified T cells can be depleted. Even if a small amount of modified T cells were contaminated in the final product, it will not have any risk to CAR's GvHD because they do not express CAR and will not survive very longer. To obtain proof-of-concept data for the novel non-gene editing allogeneic genetic platform, we chose a very well-validated target CD20 and a construct CD20 CAR using our well-characterized monoclonal antibody CAR. As you can see on the left panel, follicular 0:07:41.7 analysis of the LUCAR-20S clearly demonstrated that the non-gene-editing CD20 CAR-T cells are highly enriched in the final product after relatively simple process. CAR positive cells occupy 98.63% in the batch, while almost all these cells loss the expression of TCR complex. MLR system to evaluate the allogeneic T cell response. Our LUCAR-20S performed as good as TCR now called T cells in terms of allocate activities when encounter allogeneic simulators lymphocytes. We proposed to test the platform step-by-step and our investigator collaborating with us also suggests that before we test the full version of the allo CD20 CAR, we first test a basic version which only implemented GvHD solution in the first phase of the clinical study. So we did open an investigator initiated trial to mainly test the safety of the basic version LUCAR-20S. We have since obtained some initial data. Despite limited efficacy and CAR-T expansion were found in the first few dosed patients, no GvHD or other DLT were found in the current 300 million dose level. We are planning to study a full version of the product LUCAR-20SD. 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 allergenic CAR-T cells are 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 allogenic product can address the HvG effects. Based on a published data by leading allogeneic companies, it seems that the CAR-T expansion in the majority of patients are quite limited. And usually, the allogeneic cells only persists for 2- to 3 weeks. This HvG issue mainly hampers the deepness of response for the current allogeneic products despite aggressive immunosuppression has already been used. So as I mentioned already because IIT Legend and a PI want to first test the anti-GvHD effects to address the safety of our non-gene editing platform. So the basic version allogeneic CD20 product, LUCAR-20S was taken to the first, in-human study. It is an open-label, wait -- so here, it is open label dose-finding study to assess the safety and the tolerability of donor-derived CD20 targeting CAR-T cells administered with lymphodepletion and to obtain the preliminary efficacy in subjects who have been diagnosed with relapsed or refractory CD20-positive non-Hodgkin's 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 dosed patient received 300 million LUCAR-20S in total. So far, no dose-limited toxicity or GvHD were observed in these 5 patients and 3 of 5 dosed patients achieved a partial response. This case showed 1 of PR patients who received 300 million of allogenic CAR-T cells for prior lines 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, and a PET CT scan also showing complete metabolic response. But because remaining cancer cells were found in bone marrow biopsy, so the overall efficacy assessment was determined to be PR. Besides the LUCAR-20S, which we already starting a clinical trial without finding GvHD and DLT, we also developed an upgraded modified full version, which incorporated anti-HvG function, we call it LUCAR-20SD. In the future clinical study, we wish to have this product use in combination with a small molecule drug to tackle the rejection of HvG issue. To confirm the upgraded version LUCAR-20SD still prevent GvHD, we also performed a full GvHD assessment in a specialized GvHD model. In the experiment, our modified donor T cells or conventional CAR-T cells all successfully rendered GvHD and [ animal ] loss. Our LUCAR-20SD group labeled purple color remain staying safe without a GvHD event, just like the group of conventional allogeneic CAR-T cells. The blue line in which the TCR knockout has been performed with CRISPR-Cas9 technology. In the HvG mimic MR assay combined with the drug volume, we observed our anti-HvG strategy did shift the balance between host T cells and 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 a persistence without a need for a healthy immunosuppression. By this way, the Drug Y is a well-studied improved drug, and we will only plan to use it for a short term post CAR-T infusion. So Legend Biotech has developed a proprietary allogeneic CAR-T technology using a non-genetic approach which reduce risk of off-target activities and general toxicities. Legend Biotech also believes that this approach to the design of allogeneic programs potentially simplifies a process for our chemistry manufacturing and controls and potentially a simple -- improved product homogenetically. Based on this approach, we have developed allogeneic CAR-T LUCAR-20S targeting CD20. Our first human study was initiated for LUCAR-20S and the preliminary safety and efficacy were already observed. Legend has developed a modified version of LUCAR-20SD with an innovative armoring strategies and control host-versus-graft disease to further improve the CAR-T persistence. An exploratory trial has been planned for LUCAR-20SD. We also interested in developing CAR-NK platform to defeat cancers as we believe it process unique advantages as allogeneic products. First of all, NK cells are major components of the NK immune system and are fast killer of cancer cells. Second, CAR-NK provide a promising solution to overcome TAA escape by multiple mechanisms, including CAR-dependent, CAR-independent, ADCC-mediated killing. Third, the key role of NK and ADCC supports is combinational use with therapeutic antibody drug to further enhance of -- further response. Last but not the least, multiple CAR-NK trial have demonstrated the clinical benefit of CAR-NK cells. One particularly attractive point is a superior safety profile observed across different type of CAR-NK cells. There are multiple challenges in the CAR-NK fields. First, NK cells are short living cells, while persistency is a key for the success of a long duration response as we learn from autologous CAR-T products. Second, the most powerful NK cell expansion method is based on cancer cell lines such as K562 feeder cells. This add safety risk to the final products and also add complexity to QC process. Third, NK cell are highly resistant to the lentiviral transduction, how to introduce gene-editing into NK is a technical challenge. Fourth, NK cells are more sensitive to cryopreservation than T cells, while there are no commercial cryopreservation method is optimized to maintain NK viability. Legend has developed its multiple solutions to tackle these challenges. Legend developed a feeder cell-free expansion system an 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 developed is a well suited for current NK products, which maintains NK viabilities in a function after [indiscernible]. Let's have a closer look into the details of these unique features. The top row of this panel shows the highly pure NK product with high transduction rate. The middle row show the full expansion of CAR NK across multiple batch manufacture and representative of in vitro 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 show that Legend has a powerful manufacturing process CAR-NK from end to end. We also developed a similar scalable cord-blood NK platform with a feature of strong expansion, high purity, high transduction rate and a strong efficacy. When it comes to 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. However, previous literature suggests secretion of IL-15 is associated with significant AE in preclinical animal models. To find a signaling protease to armor our CAR-NK cells, we leveraged our internal protein engineering platform to perform in vitro and in vivo screening hundreds of rationally designed cytokine mutants. We successfully discovered our 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 manufacturing process with the following features: robust expansion in the CAR transduction process, production of highly pure CAR-NK product with strong anti-tumor activity, optimize cryopreservation process to minimize the loss of viability and the functionality of [indiscernible]. We further innovate our rational design NK cell armoring molecule called LGkine, which we found dramatically boost our CAR-NK cells. We used 7 years of development, Legend Biotech already evolved to be a leading cell therapy company. We have developed a multiple prop 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 that we believe in innovation and cooperation. While we keep a tradition of down to earth and stay low key, we work together fearlessly to challenge the technical barriers and we are well about transforming impossible to possible. Thank you for your attention, and 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 Geng, Head of Early-Stage Drug Development; Steve Gavel; Dr. Lida Pacaud; Dr. Frank Fan; and Dr. Ying Huang. [Operator Instructions] Thank you.

Congrats on the impressive progress. My name is Kelly Shi from Jefferies. So my first question is for Steve. You mentioned the late onset of CRS offers operational flexibility for patient treatment. And could you elaborate on this point? Does this refer to treated patients in all patient settings or anything more? And also regarding the exploration for cilta-cel treatment in outpatient settings, can you talk about the progress on that front? When are we going to expect data? And also, what will be the meaningful data, for example, on the re-admission rate? And I have a follow-up.

I'll make sure you guys could hear me. Thank you for the question. So maybe for folks who maybe did not hear the question, so the question was specifically around outpatient, delayed CRS, I kind of get into a little bit more detail around that and whether or not there's some data that would be forthcoming here around this program in the outpatient setting. So first of all, thanks for the question. So what we were getting at there is that one of the rate limiters in all these CAR-T programs today, and this is beyond BCMA, has been this multiple issues. One being the acute onset of CRS, whether it'd be in CD19 programs or, for example, our competitors program. And that's problematic for many hospitals. And lord knows over the last 5.5 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. So what administrators, in particular, are asking themselves is, while there's this cilta-cel program that looks like it's unprecedented in terms of its clinical efficacy. So they are 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. And I'm not just talking about the general med-type bed capacity, but more importantly, a ICU bed capacity, okay? So they're looking at the future saying, "How do I then pull through all of these patients that need this type of treatment, and can I do it in my current infrastructure? " and that answer is no. That's very clear. So the workaround and many of them have been investigating is, if I need to get this treatment to my patients as soon as I possibly can, from a mechanics -- mechanistically, what do I need to do logistically, what do I need to do? So they start moving down the road. Can I potentially administer these CAR-T programs is a hospital outpatient that would alleviate a lot of this pinch that these hospitals are forecasting to begin experiencing. So -- okay, so that's the first issue. It's capacity, knowing these big volumes are coming at the site. So the question is then how do you do it? All right. So and this is not a new issue, right? This is being investigated with CD19 when CD19 was being launched as well because those programs are also looking at fairly substantial populations. The problem these institutions run with the CD19s, and I will predict and 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 do not having a severe CRS-type reaction that may be considered to be life-threatening. So you kind of -- now -- so you're kind of limited because of the toxicity profile, right? So that's the first kind of issue in the marketplace. I was mentioning to you all is which -- kind of really unique with this program, unique to any CAR-T program is that there's this delayed CRS, average onset, meeting onset around 7 days. So 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, gives the cilta-cel, knowing that cilta-cel patients they're seeing in the clinical trials is delayed onset. So patients aren't spiking fevers. And basically -- and the protocol is very different by site-to-site because they treat different types of patients, right, in terms of where the patients live. But to keep these patients local and that definition of local changes by hospital. Some folks have -- some hospitals have resources literally across the street, some have resources within about a 10-mile radius to the hospital. So they could easily monitor these patients on an outpatient basis, so administer the product, monitor the patient and then more extensively monitor that patient as they get closer to that median. And this is the examples that they give to me in terms of what they plan on doing moving forward. So in doing that, they are not immediately admitting patients. And if you look at our clinical data in CARTITUDE-1, and Lida, can get more into that. You see that there's a very small percentage of patients that have severe CRS. The majority of them are considered to be fairly moderate. And again, the investigators who have been touching this product have been able to manage those patients quite easily outside the hospital. And I was just with an investigator last week in San Diego, and he reminded me, he said, "Steve, we're working in a COVID environment as well, continuing to be, right?" So now do you really want to bring in immune-compromised patients into a hospital today? I think not, right? So it's a fortunate situation that we have because of the late toxicity here. And what the market is playing back to me is that that's a good thing because it allows me not to admit immediately but potentially later and in essence, offsetting that length of stay that would have been -- in essence, beds and resources would have been taking up that patient is being monitored in the outpatient. So that's the concept that the market is quickly going towards. And it's funny how the market has changed on that topic from 5 years ago when I started with these programs to where it is today. You heard outpatient very -- it was kind of very seldom honestly that you hear outpatient CAR-T. I hear it all the time now. So the marketplace clearly understands that this is the future and they need to think through how to keep patients safe and treat them effectively outside the hospital. Do you want to talk about any of the data though? Yes, question around the data.

[indiscernible] Yes, so our clinical trials include patient allow, and we have kind of formulated what type of patients should be administered.

It's very helpful. I just have a very quick follow-up for Dr. Frank Fan. This gene editing free allogeneic platform is very interesting. I'm curious, is the Gene X blockade of endogenous TCR signaling is a reversible process? And also, what is the transduction efficiency of l Gene X? And do you have to do the purification for the TCR positive cells for the manufacturing process?

Yes. Thank you for your question. It is a very good question, I think. First, the mechanism is a reversible mechanism that's in serial. But while we have done tremendous experiment and setting up a very challenging environment to try to test the stability of these mechanisms. But even with very strong stimulations, the majority of the CAR-T cells, the TCR will not come back to the cell membranes. And also, we do incorporated a cell depletion process in the final -- before the final formulations because even our CAR-T, our lentiviral transduction efficiency is extremely high. We still don't want to lose a small amount of contaminated modified T cells. By the way, for the -- for one of your question, you asked about the transduction efficiency. As I mentioned already, the CAR and the Gene X has been stringently linked. Its all-in-one solution, is in the single vector connected with 2A peptide. So for any given cells that successfully transduced which is CAR, it for sure, will overexpress the Gene X as well. So the TCR down modulation will also take place. So it is completely linked the so-called 2 subtype scenarios, and we do depletion to remove esophageal is why we got a 98% over 63% -- 98.63% of CAR positivity, really for esophageal product in -- our formulations is a range of 30% to 50%. And the FDA don't like 100% of the expression CAR-T cells. But for autologous because we have that room and we -- after our enrichment, we can enrich the very high percentage of the wanted cells, but without additional risk.

I want to add to Frank's point. And with the preliminary clinical data, that Frank just presented, it actually does demonstrate that the hematology MoA is actually very efficient, even though actually that could be a -- the potential reversal process.

My name is David Dye. I am an analyst at SMBC. So first question -- a similar question on BCMA actually for Steve. The first question is just around J&J is actually developing a few BCMA bispecific antibodies. So what are some thoughts around their strategy in terms of commercializing cilta-cel versus their bispecifics? And the second question is around the sort of neurotoxicity, the delayed onset of neurotoxicity with the movement disorder you've seen. So any kind of -- any thoughts around latest mechanism around what's -- what causes those neurotox so far? And then I have some follow-up questions after.

Very good. Can you hear me okay? Okay. Maybe you'll take the neurotox question. The -- so I'm not going to speculate in terms of J&J, in terms of the BCMA program, but -- and their bispecific BCMA. But I will tell you this, the -- any new drug for the treatment of multiple myeloma count me in. So it's the best thing for patients, right? So we know going into any of these endeavors that no drug is a perfect drug for a specific patient. We know that there's different subtypes and so forth. And those numbers I was showing you earlier were eligible 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. So there's always room in the marketplace for bispecific BCMA programs as well. So I think it's fantastic, whether it be at J&J or others, to bring out other options for patients and families. So I'll kind of stop it for there. But we are -- to be quite honest with you, we are having active conversations, and we're beginning those conversations with Johnson & Johnson as it relates to their other programs. It's one of the benefits to having a partner quite honestly. And so anyways, those conversations are ongoing, so I can't really speculate too much as it relates to their bispecific. Do you want to talk about the data?

So David, I just want to add one more thing on top of Steve's comments about the J&J's portfolio. So I have very frequent communication with the J&J Jans leadership about this, and we did discuss a little bit of that. In fact, you probably will hear more on November 18 when J&J holds its pharmaceutical business review for analysts and investors. But 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 because our intention and also ambition is to bring cilta-cel all the way to the front line. And we think that, hopefully, in the near future, every patient who is newly diagnosed with multiple myeloma will be treated with cilta-cel. And that's the cornerstone strategy. And then on top of that, of course, I'll call it J&J will layer it up with Darzalex and also the 2 biospecifics they're developing. But that's a commitment from J&J and also from Legend.

Lida?

So for neurotoxicity question, so I think really mechanism of this some delayed type of neurocognitive is not really clear right now like we have a lot of discussions with external experts as well. What I can say in cilta-cel program, so we have identified what are risk factors for those events and also we implemented a strategy how to prevent like enhanced bridging therapy, for example, which was not case in the initial CARTITUDE-1 study and some other management -- patient management, basically strategies. And then what we have seen and we reported at ASCO and EHA, so those type of events significantly decreased. So we had 5% in CARTITUDE-1, and this is now around 1%. And last, what I would like to add that it's emerged as a maybe not something specific to cilta-cel, but rather more class effect of BCMA or CAR-T therapy because we know in ABECMA label, they have a case of Parkinson like case, and there is also a case of myelitis So it seems to be -- so it's indicated in a label. So it seems to be not only -- and maybe even CAR-T specific because I can go on, on this, but there is French reporting CD19 CAR-T. French [indiscernible] which also reports this type of events for CD19 CARs.

Great. Just a follow-up on sort of the pipeline program, especially on the Claudin 18.2 program, maybe a question for Frank. So did you do any biopsy on the patient that was presented? Did you see any kind of T cell infiltration and expansion within their tumors? And also, can you just comment generally on Claudin 18.2 homogenate within the gastric tumor and pancreatic tumor setting?

Thank you. Yes, as you know, the patient is in critical conditions before the CAR-T infusions. And unfortunately, I don't think we -- in the clinical studies, we have chance to do any biopsies and in the treatment of course. So we don't know how many CAR-T cells, despite we found extremely expanded CAR-T cells in the [ daratumumab ] we don't know how many CAR-T cells are in the tumor lesions. But while we -- we do have perhaps sample for ascites which would detect lots of CAR-T cells. The modern CAR-T cells, the concentration is even higher than [indiscernible]. And the cancer cells if not all gone, cell debris and then maybe dead cells of after Claudin 18.2 positive cells. So it's a very good sign in the clinical setting. However, we can do biopsies for ethical reasons. But since the patient has such huge -- 2 huge pelvic lesions and based on and I was a surgeon in my earlier career. So I can imagine there are necrosis, there are fibrosis. A lot of it -- it's not a -- for huge tumor lesions is definitely not 100% of the cancer cells. Even -- it could even -- majority of the cells are supporting tissues, fibrosis and necrotic tissues. So we never expect even with the best Claudin 18.2 CAR-T cells, we can change the tumor and the tumor completely gone within very short time. I don't think that's possible. So maybe based on my current hypothesis on my theory, 15% of the shrinkage of the tumor could be pretty remarkable already. And ultimately, very unfortunately, in the past 6 months, the lesion -- under the CT scan, the so-called tumor squ does not changed very much, remains stable. And the patient -- the condition is very well. So I'm very happy with that. So if we got a chance we would -- if -- I'm not sure the investigators will be willing to convince the patient to do a biopsy in the future follow-up. There we can do so, that will be great. I don't expect CAR-T cells still there, but I do interested to learn, what's still inside the tumor lesion, how many cancer cells are still left and can the tumor can be further shrinked. Yes. Thank you.

For the second question regarding to the Claudin 18.2 expression and the program was designed as a target therapy, and we do have the prescreening of the patient for select population. So this companion diagnostic has been developed associated with the treatment.

Right. I apologize, I forgotten your last -- your last question. Thank you Don for answering on my behalf. Yes, for -- I did look at chemistry analysis many of these patients in enrollment procedures. As for a majority of 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 Claudin 18.2 expression. Lots of them, about 19% of expression area in the area of the chemistries, which consistent what we learn from the literatures. The Claudin 18.2 is highly expressed on gastric epithelial derived cells. And so it seems for the gastric adenocarcinoma, the title bear these features, this limited specific markers and protein secretion and the really loss of it. And in a lot of literature, I remember that one Japanese literature stated extensive study on this immunochemistry when to the pair, I also presented that literature presentation in my presentation, when you pair the primary tumor with metastasis in the lymph node, you see the Claudin 18.2 is almost no case of that Claudin 18.2 in down regulated or lost. Instead, some patients even see enhancement of Claudin 18.2 expression. So that's why we repeatedly -- we're confidently saying Claudin 18.2 is a very promising target for gastric cancers and pancreatic cancers.

I just want to add a little bit more on what Frank said. If you and going back to the presentation in which the statistic actually Frank just presented and for the expression level of Claudin 18.2, it expressed more than 50% on both gastric and pancreatic cancers. However, the intensity of the expression could be varied from patient by patient. But given the unique cell of CAR-T cells, it could target actually patient expression intensity at a 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 of questions from the online participants. So we have 2 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 are likely to be more similar than different?

Yes, hopefully. Yes, so 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. So we are planning around, in essence, the same label in all the geographies that we will be selling into. The one caveat, like I mentioned to you that we're starting to observe in the United States is on the private pay interpretation of the label and also the interpretation that the private insurers are having with the NCCN guidelines, which are a little more liberal than what you see in market in terms of that fifth-line labeled indication. So we shall see, but I think -- hopefully, that answers the question. We assume the same label as our competition. But I think in the U.S., I think you'll see further evolution of how that label or how the guidelines are interpreted actually expand the market a little bit in the fifth-line setting.

We have a follow-up question. So for Lida. Regarding the potential of cilta-cel in the future frontline setting, why is there a [indiscernible] being using CARTITUDE-5 at least according to clinicaltrials.gov? Does this potentially impact the future opportunity?

So yes, thanks for the question. So I guess, yes, for CARTITUDE-5, so this is a global study, and we have discussed this with health authorities. And health authority after this discussion, current standard of care was selected as it is shown in the study. So we -- I mean we had interest to go with direct containing regimens, but outcome of discussion with authorities, we have current trial design, and that was. Yes.

Okay. I want to take one more question from online before we go back to the room. So we have a couple of questions from Morgan Stanley, Matthew Harrison. So I think this is a question for Steve and 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 LUCAR given the data you have seen in the field recently, especially CRISPR and allogen? And do you the think LUCART can deliver durable responses?

Okay. Thank you, Matthew, for the question. So I'll answer the first part, which is, what we're looking forward to updating towards the end of this year. Legend and J&J 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. So that's something we plan to update with a longer follow-up of CARTITUDE-1. And then potentially, we're also looking at the Cohort A, which is the data we presented at ASCO. But again, it's possible that we'll update with longer follow-up from CARTITUDE-2 Cohort A at a major medical meeting. And then lastly, it's possible also that we could also provide an update on additional new Cohort from CARTITUDE-2. As you imagine, we actually enrolled those cohorts sequentially. So we start with Cohort A and then Cohort B. So that's something potentially you can look forward to by end of this year at a major medical meeting. That's what we plan to update on the CARTITUDE-2 program by end of this year. And then on the second question about LUCAR given the data we have seen in the field recently. So I'll start the answer and maybe Frank will add it more. So I have two takeaways here. Number one is I like I emphasized in the takeaway 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 a very, very important key element from both regulators and also from physicians treating multiple myeloma. And I think if you look at the competition news from lately, you will see that not all the CRs are the same. And only the durable CR matters, right, and 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. And there's a scientific rationale behind that, which Dr. Fan will elaborate. But again, we don't believe that we're going to see a lot of abnormalities on chromosome or anything like that. So that's one 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 in fidelities from the process. So with that, I'm going to pass it to Frank to answer a little bit more about our allocate strategy.

Yes. I think, Ying, you already answered the question very well. The -- actually, we -- 5 to 6 years ago, while we -- in our infancy of companies, we do realize that allogenic will be the future of the cell therapy. It could be in the future. So we heavily invested. We formed a dedicated team to explore the allogeneic platforms. But after our internal consideration -- investigations, I still don't feel very comfortable going with the multiple gene-editing approach. Let alone, there's IP issues. And by that time, we are -- it's applicable to license so many IPs from different markets. So that's why our strategy is, we decided to only go with non-gene-editing allogeneic platforms. No matter it's alpha-beta T, gamma-delta T or CAR-NK. So that's why the other allogeneic CAR platforms that we presented disclosed are all non-gene-editings. It's not like we really -- so basically, I don't feel that the current hurdles like a allogeneic CAR-T is not soluble. I don't believe there is still big room for improvement. I think maybe the FDA will find it clear there -- we will resume their clinical trials after the investigations. So I think multiple different approach by development -- different companies all have their pros and cons. We have already elaborated all the pros of our platforms. But still, we are -- our program is not that advanced in terms of the clinical stage. So we want to catch it up. But we also wish the whole gene editing, the whole gene therapy field will clear all these difficulties and can really proceed. Yes. We also a gene therapy company, I believe. We're just doing ex vivo T cell gene therapies. So any -- we have to always aware of the risks that appear either in gene lentiviral - viral vector transduction or gene knockout. So we all need to have that positive attitude, but a very careful attitude to deal -- to address all these issues.

Dr. Fan and Dr. Dong Geng, we have a follow-up question from Morgan Stanley, Matthew Harrison. You didn't seem to dose-limiting toxicities DLT in your early-stage programs. Can you talk about how you are deciding on those -- in these programs? And when we could expect to see larger cohort data?

Lida?

Early-stage program in general -- yes. Frank, would you like to take that first?

So around -- pardon, the point is, we are still in the process of dose escalations. So we can't guarantee that with more patients being dosed at higher -- a higher dose levels, we won't see the DLTs, we can guarantee that. But we wish -- am I answered your question? Sorry, maybe I missed your question. Can you say it again?

Yes. So we -- so it seems that Legend didn't dose to DLT, dose-limiting toxicities level in our early-stage program.

Yes. I confirm that. Yes.

So can you talk about how...

I think from a clinical perspective -- so yes, that's true. And this trial is a dose escalation, and we will continue dose escalation in -- so I don't know which specific programs. But as soon as we don't see DLT or if we see DLT we will expand. So we will follow like the route, yes. And reporting of this data will depend, I guess, when we have meaningful number of patients with some indicative data, so we cannot comment on timing right now.

So we can see if we have any questions in the room.

This is Mikhail Keyserman from BTIG. I've got 2 questions. Maybe, Steve, the first 1 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? And then secondly, just how you ensure a good patient and physician experience? Obviously, we've heard a competitor that has been very frustrating for a lot of physicians and patients based on their very long waitlist. So how do you sort of ensure that experience? And the second question is just for Frank. If you can just touch on a little bit more on the Claudin 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 can just maybe compare those modalities? And then just on U.S. strategy, are you expecting to take this beyond gastric so looking at esophageal, looking at pancreatic tumors as well?

Ying, do you want to take supply, and I'll talk about go-to-market?

Sure. So thank you, Mikhail, for the questions. So I'll talk about the supply and then maybe Steve will talk about the launch. So obviously, it's not in our position to comment or speculate our competitors program in terms of the launch. But I can reassure you that Legend and also Janssen continue to place extremely strong emphasis and also on the above robust process and quality measures in the manufacturing discovery and delivery of cilta-cel for both clinical and also commercial supply. As you're 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. And given what we're seeing in the market based on the first launch of BCMA CAR-T, we do know that if you look at the patients who have been exposed with all 3 major classes of therapies, including IMiD, proteasome inhibitor and CD30 antibody, they face very poor prognosis, right? So given the data you have seen from BCMA CAR-T, it's not surprising to see a pent-up demand based on the first launch experience. And if there's any potential supply issues here J&J and Legend are proactive in terms of enhancing our internal capabilities to supply LV. And that's our risk mitigation strategy. In fact, we're already implementing that now today in our supply chain. With that, I'm going to pass that to Steve about launch.

Great Thanks, Ying. Yes, so in terms of, I think your question, you had a couple of questions commercially around how to manage the supply and making sure that things running smoothly at the site level. So one thing that I think I discovered early in this process, in this space, in particular, is the concept of transparency and predictability. So whatever the situation is, whether it'd be massive amount of supplies or limited amounts of supplies, the need to be extremely transparent with our providers as well as predictable with those providers. So I think some of the issues that you've been referencing in the past by other companies, I think where they ran into problems was either they weren't clear themselves on what was going to happen in terms of supply and the impact that may have. But I think there was at least some degree of non-transparency in the market. Again, I don't think that was a deliberate action at all. I think it was a matter of folks just not knowing. And as Ying said, this is a pretty dynamic space when it comes to supply. So we're approaching this. It's one of being very, very deliberate and very, very transparent with our customer group. Because of this patient population, in particular, for everybody here, I know in the room and on the phone realize the operational lift required and scheduling required to get drugs like this to patients. So you need to be as transparent as possible to our site so they could begin the planning process in order to get drugs like this to their patients. So we're in the process right now, effective today, actually of having a lot of conversations with our sites in the United States to explain them how -- to them, how we will be rolling this asset out to them. And we will continue that process for the next several weeks. But I 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. Yes, believe me, as a commercial person, I've learned way too much about operations and manufacturing over the last several years. But I think it's critical, obviously, to make these programs seamless to the customer. So we've been -- and this is where, honestly, Janssen has been an outstanding partner with us in developing an operational infrastructure that allows cross talk with our sites, focus on the commercial team, our medical team and our manufacturing team to ensure that we have this predictability across one and other 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. So anyways, there's a lot more behind that. I'm happy to go into with you maybe on the side, but that's what we're planning on doing.

Thank you, Steve. We have a follow-up question from BTIG from Justin Zelin. Would you be able to comment on the Legend manufacturing readiness and also how would that compare to our competitor?

Justin, thank you for the question. Again, Justin, I reiterated previously. We're not going to go into the detailed manufacturing capacity due to our contractual obligation with J&J on this. So I'm not going to disclose the exact capacity. But suffice to say that both partners are working very hard, again to ensure robustness and also the delivery of the cilta-cel once it's commercially launched. Frank, I think you can address the next question, which is Claudin CAR-T versus bispecific validity.

Regarding your Claudin 18.2 questions, yes, it's obviously Claudin 18.2 already involved one of the most popular immune therapy targets for Claudin cancers. And there are bispecific, there are ADCs, there are so many differentiating modalities, but all of them are antibody derived biologics, including CAR-Ts. I consider CAR-T is also a derived antibody biologics, just combining with gene therapy and T cell immunities. But if you want me to compare comment, it's really difficult because it's kind of like compare apple with oranges is still so different. In general, antibody drugs, bispecifics and ADCs, I think the innovation of neuromodality -- I mean the development of new modalities is the -- I think in the past 20 years has been vast of so much and quite immature. But maybe there is a limited room for them to further evolve. But for CAR-T or CAR-NK basically, the nature is gene therapy. There's a big version, there's no [ ceilings ] so I think for self-serve company, they can always inventing new armor strategies, armor the CAR-T cells with whatever tools they need. So relatively for cell and gene therapies there are bigger rooms for innovation for further advancing the modalities to cope with whatever questions -- whatever problems, barriers we will encounter. No matter is infiltration, is expansion, barrier whatever. So 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. So we have -- we can always keep improving it until we reach a goal to for a cancer cure. And this is completely forward-looking statement, I apologies for that. But I think you ask, I have to show my -- I still want to show my confidence. That's my personal opinion of a representative Legend.

So maybe I can add a little bit more on what Frank just said. Even though we do not know and what's the difference since we don't have data yet. What's the difference between bispecifics versus CAR-T for the -- using Claudin 18.2 as a target for the treatment of solid tumor. But for the existing data in the hematology actually field and in general, an CAR-T actually offer much more advantage than bispecific in terms actually overall and remission rate as well as the duration of the treatment because -- and from MoU perspective, its offer more flexibility. I think in the same series probably we will continue for the treatment of solid tumor as well. And as for Claudin 18.2 as a target, it already has actually grew to be a well target from the existing antibody data as well as other data. And so we believe, actually, it is a validated target for the treatment for both gastric cancer and pancreatic cancer. And we do have plan to pursue in those 2 indications in the global wide.

And, Mikhail, if I may, I'll just add 2 things. Number one, the key difference between CAR-T and the bispecific monoclonal antibodies that the CAR-T express direct killing, right, instead of leveraging the patient's own T cells by using a bispecific or monoclonal anybody for that matter, right? We actually take the T cells from the patient, yet we recognize that with a CAR. So that's where the CAR-T advantages, right, compared to the endogenous CAR -- T cells from patient population. Secondly, I know we only have disclosed so far the first patient with the lowest dose so far. But if you compare 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 the data you see from monotherapy, 1 dosing only, and this is a lower dose we have seen. We're seeing like Frank was mentioning already 6-month PFS, and this patient still remains progression free. So that's the data telling us, right?

Okay. So we have a question from Woodline Partners from Aneesh Kapur on solid, 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 time line?

Well -- so I guess I give good indication there. So we are happy with recruitment, but yes, I cannot comment more than that right now, and we will share when it comes.

So we have more questions on the Claudin 18.2 questions for Frank and Dong. So next question is from Goldman Sachs for Mike Lu. 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 due the fact that our standard FC preconditioning already did a very good job from I think the first patient we see extensive expansions. And at the peak level, 250,000 CAR-T cells per male that's remarkable month. And we think -- we don't want to really enter but maybe in the future, if we see anything -any lead, we want to reduce the depletion, that's possible. But we need the data to support whether the lymphodepletion is really critical for solid cancer programs. There is not fully -- not extensively studied in this field. We all know that for hematologic malignancies, liver depletion, precondition is critical. But in for solid cancers, I remember some investigators arguing that maybe for solid cancers lymphodepletion is not that critical. But I don't know if I agree or disagree with it, I think that we needed data to support that. But at current stage, I don't think we have a plan to vary this. We would rather put our energy on finding the optimal dose and whether we can re-dose a patient and these kind of things, yes.

So the next question is from Leerink from Daina Graybosch. How are you thinking about multiple cycles of CAR-T for your solid tumor programs? If necessary, when and how will you employ?

So I guess, I mean, yes, we have to think about this. So U.S. clinical development plan is not yet established. So we are in the process of doing that and with -- also with authorities. So I think we will do it. It depends on program by program. But in principle, I think we still try to achieve a significant benefit to the patient with one infusion. So I don't know if Frank wants to comment, let's say...

Okay. So we don't have any more questions online. [Operator Instructions]

Okay. Well, if there's no further questions, I guess I'll just make some closing remarks here. So as you can hear today, we do have a deep and wide pipeline of different programs in different technologies and also exploring different strategies to expand the field of cell therapy. And we're actually exploring multiple technologies to develop innovative cell therapy and bring them to the markets around the world. Together with our clinical development capabilities and also our global manufacturing facilities, we're building a fully integrated cell therapy platform. I hope that you have enjoyed today's presentations from my colleagues and also you share in our excitement about the future of Legend Biotech. We also would like to thank all of the investors and shareholders who have instructed us with precious capital to further our work. Thank you.