Legend Biotech Corporation (LEGN) Earnings Call Transcript & Summary

All right. Good morning, everyone, and thank you for being here for our Second Research and Development Day. I'm Joanne Choi on the Investor Relations team here at Legend. Before we kick things off, I do need to mention that today's webcast contains forward-looking statements that are subject to risks and uncertainties that could cause actual results to differ materially from the information being presented here today. These are discussed in our filings with the SEC and can be found under the Investors Section of our company website. Today's presentation will begin with an update with the latest developments in our CARTITUDE Program. Afterwards, we will take a coffee break, and then move into our R&D pipeline before opening up for Q&A. And now, I will turn the meeting over to our CEO, Dr. Ying Huang. Thank you.

Well, good morning, everyone. It's really nice to see a full room of people here. And also, I know we have a lot of investors in the net dialing in from maybe Europe, so good afternoon. And then for folks in Asia, good evening. So on behalf of Legend Biotech team, I'm very excited to welcome you all to our 2022 R&D Day. In October of last year, we knew we couldn't fill the seats in this exactly room, but we went ahead and held our first-ever R&D Day as a hybrid meeting. We made that choice because we believe that it was important for our leadership team to come together, and we felt we owe that to you, investors, shareholders and analysts, to give you the most comprehensive view of the pipeline that we're delivering. So while the doors to most businesses were still reopening, our teams of researchers, scientists, technical operations specialists and engineers were busy at work all year long. And we wanted to use an R&D day to tell you why they're showing up every day. Of course, it was in part because of cilta-cel, or now with a brand name CARVYKTI. At that time, cilta-cel was our lead product candidate and is now approved as CARVYKTI in the United States, Europe and also just most recently, in Japan, for the treatment of relapsed and refractory multiple myeloma. We were gearing up for our first product launch and significant clinical developments in the CAR-T Program, which we run in partnership with our colleagues at Janssen Pharmaceuticals. Yet our R&D team was also at work on several promising agents within our pipeline. We are focused on harnessing our broad ambition to realize the potential of cell therapy, and to do so in serious illnesses such as gastric cancer, hepatocellular carcinoma and non-Hodgkin's lymphoma. We're excited to show you today where those efforts are going, and we hope we will encourage you by the remarkable progression of our pipeline programs. Along with our partner, Janssen, we are launching CARVYKTI, but we're also working hard to realize the next frontier of cell therapy, which goes beyond CARVYKTI. Despite the challenges, we're making inroads into solid tumors, including gastric cancer and colorectal cancer, which are among the lead causes of cancer deaths in the world. Just this summer, our IND program application evaluating LB1908 in adults with [indiscernible] gastric and esophageal cancer, was cleared by the U.S. FDA. We're now preparing for that trial, and we look forward to launching it early next year. We're also actively exploring allogeneic platforms to create new cell therapies. We recognize the potential of allogeneic cell products to address the issues of scale and capacity in CAR-T. And we hope to be the ones that prove that allogeneic CAR-T can become a mainstream treatment in the future. Today, our Head of Research and Early Development, Dr. Guowei Fang, will walk you through several programs that we believe will help us achieve this scale and position Legend well. Why rely on the CAR-NK technology, while the other one is a CAR Gamma-Delta T platform? As a company, we have always been technology-agnostic, and we're better positioned than ever to push the limits of the cell therapy on that lead. Before today is over, you will learn more about how we're doing that, and you will hear also from several of my colleagues on what lies ahead for the remainder of the year and also in 2023. So first up is Dr. Lida Pacaud, VP and Clinical Development Head; and also, we have Steve Gavel, VP of Commercial Development and Head of Commercial Operations here in the U.S. and Europe. They will share updates on our BCMA Program and touch upon the clinical and commercial plans for CARVYKTI in newly diagnosed patients as well. And then Dr. Guowei Fang is a new face this year. So he's the SVP and Global Head of Research and Early Development at Legend Biotech. Dr. Fang will outline our R&D pipeline, including programs in solid tumors and allogeneic cell therapies for hematology malignancies. Again, thank you very much for joining us today, online or off-line. I hope that you will enjoy today's presentation and share our excitement about the future of cell therapy at Legend. With that, let me give the podium to Lida.

Thank you, Ying. Welcome, everyone. I will start with Cartitude Program, clinical development program. I will start highlighting some of the recent data we have reported this year, and then I will focus on ongoing clinical trials. We have participated in many conferences like ASCO, European Hematology Conference, IMS, as well as we made some publications. First to highlight updates of LEGEND-2 study, so this was a proof-of-concept study by investigators in China, which was basis of transfer of this program to global development and collaboration with Janssen. LEGEND-2 study investigators published now 4-year follow-up data, so this is in the journals, and we do continue to see in these patients sustained benefit from cilta-cel. You can see here progression-free survival as well as overall survival, so half of the patients are past 4-year follow-up now and sustained benefit of the patient's median overall survival has not been reached. And when we also look to the patient who achieved complete response after CAR-T infusion, their PFS as well as overall survivals at the top of the top line on the picture here, are very sustained in the range of 75% for survival. In terms of global programs, everyone is very familiar with CARTITUDE-1, our registration study, which served based of all worldwide approvals. And then we have CARTITUDE-2 multi-cohort study, which explores different settings of early or relapsed/refractory different patient population and subsets to inform us in our Phase III studies. So that's CARTITUDE-2. And then we have 3 Phase III study, CARTITUDE-4, which is in patient with 1, 2, 3 prior line [indiscernible] in lenalidomide refractory, and CARTITUDE-5 and CARTITUDE-6, those are studies in frontline myeloma. For CARTITUDE-1, we did present and published as well in JCO, median of 28 months follow-up, long-term follow-up data. So it's 2 years post last patients. So all patients have 2 years follow-up or greater, and median follow-up for this analysis is 28 months. [indiscernible] publication. We did see, of course, response rates. I think, our audience is familiar. We have 97% of overall response rate and stringent CRs are 82.5%. We have reported responses are deepening over time. So increasing in terms of like VGPRs, evolving in CRs and CRs evolving in stringent CRs. More importantly, with this updated analysis, we also reported subgroups with high risk characteristics, and we did see consistent benefit in those high risk [indiscernible] for example, cytogenetic abnormalities, ISS stage, high tumor burden or presence of plasmacytomas. These are curves from that updated analysis, and if we focus -- so it represents group PFS as well as overall survival. If we focus on blue curve on the left side, so that's the patient who achieves Tringen CR, and these patients have -- like overall population is a purple, but if you look to the blue curve, [indiscernible] CR patients are doing better. And then even more importantly, if we look to the top 2 curves on the left side panel, so these are patients who have sustained the MRD. So MRD sustain for more than 6 months, that green line and then more than 12 months. And we see even greater benefit, which speaks of value FMRD negativity. And as you know, in this trial, 91% of the patients who were available MRD negative. So MRD negativity definitely is a very predictive of sustained median PFS and survival. So safety, we did start reporting some more long-term characteristics of safety. We did 16 patients having SPM, so secondary primary malignancies. Those were arranged some hematological malignances in 9 patients with low grade lymphomas or MDS and AML. So some patients have MDS, which then also in AML. And then there are some non-hematological malignancies. These numbers are probably expected because we know that these patient populations of these prior 6 lines of therapy heavily pre-exposed to alkylating agents, which is melphalan, 83% of the patients were [indiscernible] as well as it has primary second malignancy rates in between like 5%, 10% from this treatment alone. So right now, our investigators, we do not have any concerns. We continue to monitor and patients live longer. So these rates definitely is acceptable based on our discussions. We did report 1 case of Parkinson-like symptoms, which occur, so this is a new case in Day 900. This patient is stable in terms of Parkinson's syndromes and functioning adequately in the life and continues to be stringent complete remission. And as we have reported, we did implement this Parkinson-like or neuro movement in neurocognitive type of disorder. So we did implement it measures. So we have seen some factors like tumor burden, cell expansion and CRS, neurotox, for example, risk factors to see this event. So it was high rate in CARTITUDE-1 study. But since CARTITUDE-1, we have treated over 200, even maybe 300 patients now, and incidence of these type of events is very low now 0.5%. And we also know the Parkinson-like case has been reported in another BCMA CAR-T, as well in the FDA label. I think with this, I will hand over to Steve.

Thank you, Lida. Can you hear me? Okay. Thanks. Good to see everyone. It seems like since last year, we've got a lot more folks in the room, and I know in speaking with folks who have organized the meeting, we have a lot more people on the line. So what I thought I would do is just go over some numbers with you. So I apologize for folks who may have been in the room last time as this will be a little bit repetitive, but I do want to go over some of the market opportunity assumptions that we are making as it relates to our initial indication in the CARTITUDE-1 trial. As I had mentioned in his opening remarks, a lot has gone on over the last 12 months in terms of regulatory approvals. So on February 28, obviously, this compound of CARVYKTI was approved. Just as a reminder, this is a fifth line indication. And in terms of an eligible patient opportunity, our estimates -- our assumptions we're working on is about 12,000 patients that will meet the eligibility criteria for a fifth line indication in the U.S. We also received approval in May 25 in Europe. In Europe, just as another reminder, that's a fourth-line indication as opposed to the fifth line indication here in the states. That represents roughly about a 6,000 patient opportunity in terms of eligible pool. And then finally, you heard from Ying, we just received an approval in Japan on September 26. That, like Europe, is also a fourth-line indication. That represents approximately 4,000 patients that meet the eligibility criteria. Before I go on to the next slide, I just want just to kind of qualify what these opportunities represent. This is patients that, in essence, meet the eligibility criteria. Often after the conference, I get a lot of questions about is that a treated population? That doesn't necessarily represent a full treated population. There's a lot of discounting and so forth that come off these numbers, such as fitness levels, et cetera. But I did want to give you those top line numbers because I'm often asked for them. Okay. So Ying had mentioned, obviously, we launched in February, late February, I wanted to talk about a little bit about our relationship with Janssen, as well as some of the things that my team is actively involved with the launch here in the U.S. So again, maybe for some of you who may not be familiar with the Janssen relationship commercially, we're 50-50 co-promote equal. Here in the United States, the way that we are structuring our commercial group or groups across the collaboration. Legend is basically -- our commercial footprint is residing within the institutions that we are certifying. Often, the question I often get is, well, how many sites have you [indiscernible]? In the United States today, we have roughly about 40 sites that have been certified to administer CARVYKTI. It is our intention to raise that number up as we launch, and you'll hear about CARTITUDE-4 in a moment from Lida, up to 70 to 80 sites. So we'll be rapidly increasing our site coverage here in the U.S. as we start rolling into that second indication. Since launch, the demand has been so great. We've been actually outstripping supply. So many of you who have been covering us for quite some time are aware of that. Because of that, we basically changed a bit our commercial strategy in terms of how we intended to roll this asset out. We're phasing this program over time. Really, the key tenet that we are adhering to is to ensure that we are very predictive in our supply to sites that we are certifying, and that they could then obviously base their planning decisions and their patients' decisions based upon our supply. So I wanted to make note of that. Outside the United States, the way the collaboration works is Janssen will basically lead all commercial activities and deployment activities with the exception of China, where we take point there. I did want to just end this first point around CARTITUDE-1 around 3 different areas, around the positioning of this asset, and this is global positioning. One thing that is coming through loud and clear as you would expect, you heard Lida go through the efficacy data and the fact that our median PFS is yet to be reached, we are clearly the winner here in this class, and it's what's driving that demand so high, of course, and we're working fee virtually to remedy that situation from a manufacturing perspective. But I did want to touch on this issue of operational flexibility. The other thing that is resonating very clearly is not only are we the clear winner in terms of the efficacy and safety profile for this asset. What many of the sites are also drawn to is what we call operational flexibility. We see with a delayed CRS profile with this asset and our toxicity profile that is, we're starting to notice and many of our sites are now moving to administer CAR-T in a hospital outpatient setting. That's very important as you start rolling into and looking at much larger patient population, and we'll talk about that population in a second in CARTITUDE-4. Because right now, sites need to look at ways to scale on their end, and they're looking at our operational flexibility in terms of outpatient administration as a means to getting there. And then finally, from a patient access perspective, this product is available very widely across all of our commercial, as well as government payers in the United States. So we're very proud of the work that our partner, Janssen, has done in that regard. So with that, I think I'm going to turn it, I think, back to you.

Right. So we will continue with late line setting. We did this close our CARTITUDE-2 core data at IMS Conference in August, and as well as we published in a journal in [indiscernible]. So this is a court of patients. So you may remember this multi-core study in cohort C here. So these are patients, basically our same population as CARTITUDE-1, but in addition, patients are pre-exposed to prior BCMA therapy, noncellular prior BCMA therapy. So it's basically antibody drug conjugate or bispecifics -- this is efficacy results from cohort C. On the left side, we see a prior ADC group. And on the right side, prior bispecific group, we had 13 patients in ADC and 7 patients in bispecifics. We did see roughly 60% of response rates in these patients, median follow-up here is 11 months. Importantly to note, 80% of the patients of these patients were refractory to those prior BCMA agents. And yet we still achieved 60% of response, which is definitely a benefit for these patients. These patients had a median of 8 line of therapies. So it's again compared to CARTITUDE-1 which is 6. So it's much heavily pretreated population. In terms of safety, nothing really to note because we did see serious neurotox in line like start of CRS in average 7 days. All grade duration of serious or neurotoxicity events are comparable to CARTITUDE-1. We did not see any neurocognitive or Parkinson's-like adverse events in this group of patients. So overall -- and then of course, there were some days which accrued 1 treatment-related, and others, no treatment related or due to progressive disease. So overall, this data tell us that in more heavily pretreated patient population compared to CARTITUDE-1. Safety profile remains consistent, as well as cilta-cel had favorable risk benefit in heavily pretreated patients who were 80% refractory to prior BCMA. So now I would like to move to earlier line settings, so 1, 2, 3 prior lines. And we have 2 data sets, so the CARTITUDE-2 Cohort A and CARTITUDE-2 Cohort B. These are data 20 patients each we have reported. And this is a population of 1 to 3 prior lines, and which is also informing us for our ongoing Phase III study, which is CARTITUDE-4 study. Again, to highlight Cohort A, our patients who exactly same population, actually as CARTITUDE-4, patients who have 1 to 3 prior lines of therapy and lenalidomide refractory, and Cohort B are patients who had early relapse within 12 months after frontline therapy or after frontline autologous stem cell transplant. This is results for Cohort A. We did see 95% of response rate and more than 90% of complete response rates. So the data are very consistent here. We have 17 months of follow-up, and are very consistent with CARTITUDE-1 and informing us for our Phase III study. In terms of safety profile remains manageable and similar going to CARTITUDE-1. We did see, it's not shown here, CRS neurotox is similar in terms of severity grades. We did see some maybe better resolution of cytopenias. So we have reported that, and cytopenias are very important because these are patients in earlier line and recovery of cytopenia trends to be slightly better in this earlier population. So this is Cohort B. Again, we see 100% of response rate, 90% of the patients are more than CR. And here, we had 13 months of follow-up. So totality of this data or these 2 cohorts lead us to our ongoing Phase III study. CARTITUDE-4 is a randomized study with 400 patients, with 1:1 randomization patients in control arm are receiving PVD and DPD as an investigator choice. So these are treatment regimens. We selected base of current practice and try to meet more like a worldwide standard of care. And in CAR-T arm, there is bridging therapy, which can be 1 or 2 cycles of the same regimen of PDD or DPD. And then conditioning with lymphodepletion and cilta-cel infusion. After cilta-cel fusion, there is no treatment. So there is this observation when in comparator arm, patients are continuing PVD or DPD therapies until progression. I would like to highlight the key inclusion criteria I mentioned. But also to highlight, yes, we require prior proteus inhibitors and inmates exposure, as well as daratumumab exposure. But a patient does not need to be daratumumab exposed. So this is also different from new [indiscernible] study is reported actually at least in press release. And there are differences between this trial. So 1 is our trial here is 1, 2, 3 prior lines when [indiscernible]. So CARTITUDE-4 is 1 line earlier. And second is we do not require daratumumab pre-exposure, so which is probably important, because there is still a good proportion of patients worldwide in United States or elsewhere who are not getting data tumor in very early lines. And this study has fully enrolled. It's worldwide and it's even driven primary endpoint. We are waiting for primary endpoint, and we will report when a number of events we need this reached. This is a summary of current literature, which can give indication how these patients are treated currently and what outcomes they have with current treatment. And you can see different studies here. Then again, it's lenalidomide refractory population, right? So like [indiscernible] or [indiscernible] study as patients are getting 9 to maybe 12 months benefit from current treatments. Okay, Steve?

Yes. Thank you, Lida. So I'm extremely excited about this study for a number of different reasons. The big reason, and Lida mentioned this, right, so this is in a 1 to 3 prior lines population. Strategically, what we intended to do with this brand is drive the brand market share, it's brand awareness in this initial indication in CARTITUDE-1. But in that sense, CARTITUDE-4 allows us is, in essence, to leapfrog, the current [indiscernible] that's in market today. So we're assuming, as Lida had mentioned, an indication that will come on the backside of next year, into 2 to 4 prior lines of therapy, we'll be coming in at a 1 to 3. So in essence, be able to leapfrog in front of the existing CAR-T in market today. It's an extremely important piece. The second piece behind this, and I'll get into the opportunities in a second here, and I can't state this loud enough is the lack of daratumumab requirement. In other words, we do not require dara exposure as part of this indication. That's extremely important because today, about 80% of all patients in second line today are not dara exposed. So that's an extremely important piece of this study that you see a dara exposure requirement with bema. So very important from a modeling perspective in terms of eligible patient population, which leads to the next point on this slide. So in the United States, we're anticipating about 36,000 patients will meet the eligibility criteria for this indication. That's a 3x increase, which you saw in our initial indication. This is a major inflection point for this brand and will continue on as being a major inflection point for many years. In Europe, this indication will represent about 16,000 patients, and in Japan, about 5,000 patients. We're not giving guidance yet around CARTITUDE-4. But as I mentioned earlier, one of the key elements of our launch is to expand this commercial footprint to accommodate 36,000 patients in the United States. So you will see, for this brand, a rapid increase in terms of what we call our site certification or commercial footprint, going from 40 up to roughly 80 very rapidly to accommodate this particular opportunity in the United States. So with that, I will pass it back to you.

Okay. So now we are moving to a newly diagnosed setting, and I would like to explain what we try to achieve and how we try to achieve helping patients in diagnosing and where do we see role of CAR-T therapy with our trials. First, the treatment, this is really to set a background here to understand how patients in newly diagnosed settings are treated in [indiscernible]. Patients are characterized as transplant eligible based on age and comorbidities, vital organ functions. So this myeloma is a disease of relatively advanced age. There is a significant proportion of patients who will not be physically fit, or by age criteria, different countries, different institutions have like a different definition of it, but age and comorbidities, organ functions and frailty index are criteria which you define if patient is eligible for transplantation. If patient is eligible, then they undergo induction therapy, which is usually 6 to 8 cycles. Then there is high-dose chemotherapy conditioning with melphalan, which is a very strong treatment, of course, and requires after transplantation, patients have long hospitalization. It has a lot of comorbidities, infection, cytopenias for months, at least, if not more. So that's a very -- from a patient perspective, quality of life perspective and comorbidity and adverse event risk perspective. So this is -- and then after transplantation, patients may still receive 2 cycles of consolidation depending what is outcome after transportation in terms of response, if it's completely response partial, et cetera. And then there is also plus or minus maintenance therapy in some high-risk patients. What we try to achieve with CARTITUDE-6 is to -- basically trial is going ahead of transplant, right? So we try to save patients from autologous times in transplantation and high-dose condition. There is another option CAR-T can intervene really after transplantation in patients who have no optimal response. So that was another option. We have thought about that. But I think with the product profile, we see a very long sustained PFS we see with cilta-cel, we developed this program CARTITUDE-6 in head-to-head to transplant. And then lower part, we see transplant in eligible patients or patients who are deferring transplant, they would undergo against cycles of induction and receive maintenance therapy. This is a CARTITUDE-5 target population. So after induction, basically, we are consolidating with 1 infusion of CAR-T onetime treatment. In terms of this latest transplant ineligible or trust at deferring population. I would like to explain. So there are patients who are not eligible because of this age and comorbidity I mentioned. But there is also a change in clinical practice we see that there are more and more patients and physicians who are choosing to defer transplant and not to undergo it in frontline. So they are deferring it to second, third line and not front line, and there is a reason why. There is SWOG-077 study. So this study has reported VRD regimen in transplant in patients who would be eligible for transplant, but did not decided not to undergo transplant. And this had no basically had similar outcome to transplantation. So this trial was not randomized versus transplant but showed the same PFS benefit. It always benefit as transplantation. And more importantly, the second study, which is shown diagram here, so this is in IFM, International Foundation of Myeloma study. So this is random study when patients you see on the diagram, right, so they have VRD treatment and then 1 arm. They decided not to receive transplant, and then second arm received transplant in frontline. Outcome of this study is that PFS is different, right? So this first PFS. However, overall survival is no different in this patient. So this paper -- I think this Phase III concluded an influence clinical practice is that patients are -- physicians more and more are choosing not to take transplant in front line. And we also checked on this in databases like this is cancer impact database to see what is happening in real practice. And this is confirmed. So basically, what we see that 50% to 60% of the patients that we show here in U.S. and Europe who will be transport not eligible. So that's not eligible because of agent cover BDP. But then the remaining patients who would be eligible for transplant, there is 38%, 32% we will decide to defer by choice, and then remaining one, 60% who would be eligible transplant will undergo transplant. So now I think to go in, again, give you more details on our Phase III studies, and I will come back to this transplant practice that, so this CARTITUDE-5 is transplant ineligible patients or patients who are choosing physicians and patients choosing to defer transplant, and patients who undergo [indiscernible]. It's 650 patients study. Patients will have VRD induction in both treatment arms, so 2 cycles of VRD, and then maintenance by RD in control arm when cilta-cel infusion will be given in CAR T25. And here, again, there is no treatment after cilta-cel infusion, so patients are in observation and treatment-fee versus control arm who is continuing movement texametasone maintenance. This study is ongoing in a very large study worldwide with very high interest. We are recruiting very fast. And CARTITUDE-6, this trial going ahead comparing to stem cell transplantation. And this, as I mentioned, these are patients will receive DVRD as an induction regimen and after transplantation. So total each arm, if you look, will receive 6 cycles of DVRD. So in controls arms, it's 4 DVRD transplantation, and 2 DVRD in cilta-cel arm, it's up from 6 cycles and then therapy with cilta-cel. Here, we have revalued maintenance in up to 2 years. So this is, again, outcome of different country practices. And we decided to suggest to have Revlimid up to 2 years. However, we know Revlimid tolerance. It has been reported. Some patients are not able to tolerate that long. But that's what protocol is designed. This study is actively opening, so not yet recruiting, but opening, and this is also studying collaboration with European myeloma network. But this is not a European study. This is global starting. So this is to summarize how we see a potential role of CAR-T therapy and this database and clinical practice data, I have shown you, so this is really conceptual. This is not how commercial, how many patients will be used, but this is what is clinical practice right now. So if you take 100 newly diagnosed patients, 50% to 60% will be transplanting eligible, another 15% will be deferring it. So that population basically goes in CARTITUDE-5. And then remaining 25% of the patients who will receive transplantation will be going in CARTITUDE-6. And as I mentioned, we are intervening much earlier in the course of disease, then there is patients who is 13 middle small bid box here, 30% to 40% patients who received transplant may have suboptimal response. Of course, this is unmet medical need group. But we do see CAR-T role earlier than that before even patient receive transplant. I think, Steve, back to you.

Lots of numbers. So frontline, Holy Grail. We're always being asked when are we going to go in frontline. So CARTITUDE-5, right, so you've heard from Lida, CARTITUDE-5 represents growing populations, folks who can't -- who are not candidates for transplant and folks who are but are deferring for different reasons. So from a market perspective, it's a much bigger population than once with [indiscernible], just because of the current modalities that are in market today, especially the United States. And Lida mentioned and described some of the studies that compared drug therapies versus existing transplant and you saw how well those patients did who are receiving triplets, et cetera, upfront. So let's take a look here. So CARTITUDE-5, so 64,000 newly diagnosed patients across the 3 regions, U.S., Europe and Japan. So this transplant not intended, right? Those 2 segments that we just discussed, represent the U.S. about 17,000 patients; in Europe, about 9.5, 9,500 patients; and in Japan at 3,000. I mentioned this last bullet, I think it's extremely important. We're getting a lot of feedback on this study from our payers, in particular, commercial payers. So the good news, and the reason why so many patients are deferring transplant, we saw the efficacy results with the upfront therapies. But with those upfront therapies also comes incremental cost over time, right? There's the cost of the upfront triple or quad depending upon what that physician is choosing for that patient, but also maintenance. And when you take a look at that, the cost of that and start comparing it to a one-in-one therapy, or a potentially one-and-done therapy, the cost differential can be significant even with the cost of CAR-T therapy, and we all know that, that is not insignificant. But when you take a look over the life of that patient, you start to see tipping points in terms of just purely from a cost perspective. The second thing I think it's important, and I don't know if Lida mentioned this, is that one of the other reasons why patients defer even though they're eligible, if you've ever talked to patients who've received transplant, they'll tell you, it's one of the worst experiences in their life. So from a quality of life where you do not have to go through that experience like transplant, and as patients and physicians become more familiar with CAR-T therapy, from a quality of life perspective, it makes a whole lot more sense. And you're going to see this, I think, over time, physicians as well as those patients will start opting into CAR-T therapy that may have been deferring transplant. At least that's what our models are showing us. So I want to make sure we touched on that. I think we're going to turn it over to -- I think I have 1 more. Sorry. So the Holy Grail versus transplant, CARTITUDE-6. So this is the first Phase III for CAR-T therapy versus transplant. We're obviously very excited to see this study given the fact that no other CAR-T has gone up against transplant this way, at least BCMA CAR-T. So I mentioned already about the economics, who they play out, and obviously, this transplant population as well, but I also wanted to give you some ideas of relative numbers, right? So again, 64,000 newly diagnosed across the 3 regions. This is the breakout in terms of eligibility for the indication by region. So 10,000 U.S.; in Europe, 8,500; and in Japan, 1,000. And again, as I mentioned, we run on a post in this study. So there are no other CAR-T therapies, studying CAR-T in BCMA, upfront against transplant. So this ought to be very interesting to see how this plays out once this data is published. So with that, I think we're going to turn it down to R&D, or are we taking a break right now? Yes, I think we're taking coffee break.

For those joining virtually, we'll return in about 15 minutes. Thank you. [Break]

Okay. Hello, everyone. Lida and Steve just gave an update on the clean development and commercial side, and it has been a very busy and productive for a year. On the research and early development side, it also has been very busy and productive. I'm very excited about -- to provide an update today. So I'm going to divide the update into 3 different sections and first provide an overview for our R&D strategy, our technology platform and also describe our end-to-end capacity in cell therapy. From there, we will dive deep into our program in solid tumor, our platform in allogeneic therapy and then also introduce a new product program in the allogeneic platform. So in the past 3 years, cell therapy as a field has made a tremendous progress and accomplished substantially. 6 products has been approved by FDA, including our breakthrough CARVYKTI product. Our goal is to -- from the research and early development perspective is to continue to realize the full potential of cell therapy. To achieve that, there are quite a few hurdles we have to address. On the tumor side, it's the antigen heterogeneity, it's an immunosuppressive environment and also the disease pathology. On the cell therapy product side, the constraint includes the insufficient immune cell expansion persistence, trafficking infiltration, treatment-related toxicity, a very complex manufacturing process, high cost. Allogeneic platform also comes with its own challenge, including GVHD and allogenic issues. So as a sale side of the company, our overall R&D strategy is geared towards addressing those major challenges. This slide just outline our current strategy. First, this is a complex therapeutic modality. We need to invest in research to understand the disease, understand immune biology. From there, develop various mechanism to target the disease itself, target the immune mechanism and in the form of developing novel armor. And then for allogenic program, we need to address GVHD and allogenic issue. In terms of platform and product design, we want to establish -- differentiate the allogenic platform in the form of Alpha Beta [indiscernible] and Gamma [indiscernible] we'll share some of those progress at today's presentation. Once we have a differentiated platform, we want to quickly move into allogeneic product research and development. We focused on 3 major blood cancer diseases, initially, multiple myeloma, AML and the non-Hodgkin's lymphoma. We will continue to explore the solid tumor space. with the right target, right diseases. For our product design, we want to generate or engineering individual product tailored to the disease passage addressing the unique immunosuppressive tumor micro environment. The product can come in the form of [indiscernible] as well as allogeneic form modality. The cell therapy is a very complex treatment modality and preclinical evaluation only can provide certain level of information. We need to validate different platform and product in clinical setting. And we will continue to use the investigator-initiated clinical study to fast track the proof of concept. From there, continue to develop product in R&D and regulatory trials. Just to sum up, we are interested in both hem malignancy, as well as solid tumor in the form of autologous and allogeneic product design using diverse modalities such as CAR-T, [indiscernible] and [indiscernible]. Exactly which platform to use is going to be tailored by the immune mechanism and by the disease itself. We are happy to report that we have heavy investment in all those areas, which gives us options and choice to design optimal product. To achieve our R&D strategy, we have been very busy in the past 8 years to build various box. So starting from the antibody discovery generating water-specific CAR design, we take heavy learning from our success of cilta-cel, try to understand and then optimize the CAR-T design so that we can enhance the immune [indiscernible] structure and optimize the immune activation mechanism. Those CAR activities here are further documented by the unique armor mechanism. We have been developing internally for [indiscernible], we focus on 3 areas to drive the immune cell expansion persistence, to enhance the immune cell trafficking infiltration as well as to overcome the tumor microenvironment. [indiscernible], we focus on 4 different categories, which I will share in the subsequent slides. [indiscernible] in the form of cytokine anchored mutation engineering as well as into see that. We also focus on the immunosuppressive tumor microenvironment and using armor mechanisms to address that. Our effort in immune modulation of immune engineering go beyond adaptive immune response, but also take advantage of [indiscernible] immune mechanism, as well as more engineering [indiscernible] signaling and the functional circuit developing the intercell modulate. Some of those are mechanisms can also apply to the allogeneic platform as currently we are doing, and we also developed various strategy and engineering effort to address the GVHD and the rejection. Let's talk about the brand itself. We have internal antibody discovery and protein engineering capacity, mostly focused on the single domain binder, VHH base. This type of bundle is being used in cilta-cel, and it provides opportunity for us to improve the CAR expression and stability, allow us to access membrane proximal actives. And those small bundles also give us opportunity to engineering complex, more-targeted CAR construct. Equally important, so that engineering process, we can optimize the synapse to enhance the immune cell activation and the response. Next, I'm going to spend a few minutes talking about our effort in the armor mechanism because this is an important component for our cell product. Let's focus on the cytokine for a minute. We all know that cytokine are very potent immune regulator, which can activate immune cell response. And yet this systemic exposure of cytokine can generate systemic toxicity. And therefore, our engineering effort on cytokine is focused on a good balance of efficacy versus safety. Improving the safety profile is a high priority for us. And this slide, industry, the 1 example, for example, we can take atopic expression in the cytokine and then anchor to cytoblast membrane, cytokine can then signal back through the endogenous receptor in autocrine mechanism, and therefore, actually the immune cell response. As you can see from those 2 illustrative data point, indeed, those memory anchored cytokine can further enhance the immune response and drive for the immune cell expansion. At the same time, given that it's memory-anchored, it would also reduce the systemic exposure and improve the safety profile. We can even go 1 step further beyond this. We can track the ectopic expressed cytokine. Intracellularly, devices reached the sales memory, and this actually is a very interesting and now that we engineer cytokine. If you look at those 2 data panels, indeed, intracellular [indiscernible] to cytokine have better cytotoxicity against tumor cell compared to screen cytokine. And yet interesting enough, the [indiscernible] has lower expression, both intracellularly, as well as secreted form compared to free-secreting cytokine. Again point to the benefit of balancing the safety profile at the same time, drive for a potent immune cell activation. For solid tumor program, we need to address the immunosuppressive tumor microenvironment. One way to approach that is to use dominant active receptor molecule, which can still bind to the immunosuppressive ligand, but block suppressive signing mechanisms. In this slide, indeed, those dominant active constructs does work in the form of suppressing the signaling inhibitor immune cell in the middle panel. And then you look at the functional consequence by expressing the dominant inactive trapper, it can further drive the immune expansion on the right side. And what's a bit unexpected for us is that those trapper molecule, not only enhance the immune cell activation prevent exhausting, but at the same time, it's promoted immune cell infiltration into tumor microenvironment. In terms of blocking immunosuppressive signal, we can do 1 step further to use hybrid receptor molecule where we have actually cell the ligand binding domain, recognizing the immune signal and then link that into intracellular domain, which activate the immune signaling and the promoter immune expansion. And this is the so-called the switch receptor. As you can see from the middle panel, indeed, this type of switch set block immune inhibitory signaling, but at the same time, activating the immune -- activating signal. Functionally, it provides stronger cytotoxicity in terms of tumor cell kidney. In the immune mechanism is another area, we invest heavily in the past 2 years to take advantage for the synergistic interaction between adaptive and innate immune mechanism. As we know that in the immune mechanism, our first line in defense, and they are fast and effective in terms of response. They also can communicate or signal to the adaptive immune cell. So we take advantage of this unique immune mechanism to incorporate into our cell product design. One example is illustrated here. On the left side of the diagram, it's a traditional CAR design, upon the tumor cell engagement, activate adaptive immune response and drive the cytotoxicity. On the right side, it's armor, which coupled tumor energy engagement to the activation of innate immune response, leading to secretion of cytokine, which can then feedback in auto [indiscernible] signal fashion to drive the immune cell expansion persistence. Some of the user data was issued here on the right side, showing that increased cytokine secretion, as well as more robust immune cell expansion. Lastly, immune cell fitness is another key issue that we need to address in oncology settings. Immune [indiscernible] from the cell therapy product has to be able to survive and function in a harsh hostile tumor micro environment. And therefore, we try to identify intercellular mechanism, which can promote the cell immune cell fitness in the presence of little oxygen level, in the presence of limited nutrient condition. So this is in-vitro screening process. We take primary T cells, coupled with [indiscernible], the functional [indiscernible] we need to identify key rectory circuit, which enhance the immune cell function. So this effort, we identify a fairly -- a large list of candidate molecules. Some of those are validated and shown here, the intercellular modulator 1 and 2. They drive higher cytotoxicity against tumor cell and then also more robust antitumor activity in vivo. We just want to use those examples to illustrate our research effort in order to win, to maintain a leadership position in the cell therapy space. Those give us a diverse true box to optimize our cell product engineering. And with those 2 works, we quickly build an end-to-end R&D capacity from the identification, validation, with target engineering and binders, incorporating into the CAR design and armor design. From there, we developed a robust in-vitro, in-vivo assay pipeline to really assess the efficacy and the safety parameter of those candidate cell product. Coupled with our internal CMC manufacturing process, we can efficiently advance those molecules into clinical study in the form of both [indiscernible], as well as R&D study, engaging external KOAs to accelerate the product development process. With this end-to-end capacity, we have been building a robust pipeline across the entire research, discovery and development space. And some of those programs we introduced last year, where we'll provide an update, 3 program, we will provide an update today in terms of current development stage, which is autologous CAR-T product targeting cloud 18.2, GPC targeting liver cancer and DLL3 targeting small cell noncancer. We will introduce a new program today, autologous program, GCC targeting colorectal cancer and other gastrointestinal cancer indications. We are also very excited about the allogeneic program, and I will provide an update on those platform development, as well as introduce a new program -- new product programs. So let's focus on solid tumor. LB1908, 2101, 2102, was introduced last year at the R&D Day. We will provide an update on those 3 programs. Let's forget 1908. This is autologous CAR-T targeting cloud 18.2. 18.3 is a familiar target to this audience. It's component of tight junction and highly expressed in gastric cancer and pancreatic cancer in addition to other solid tumor indication. It also has some lower level expression in normal gastric tissues. We identify internal binders, which specifically recognize cloud 18.2 with high affinity. And affinity or the selectivity of this fund is dams in terms of its differentiation differential binding to cloud 18.2 to 18.1, which is a close homologue for 18.2. Our binder only recognized 18.2, which is a unique differentiation against some of other product in similar space. This product is currently under investigator initiative study in China, targeting CAR-T 18.2 positive patients with the recurrent and all metastatic advanced solid tumors. Those patients are already fall [indiscernible] with therapy, systemic therapy have very limited treatment option. The enrollment for R&D studies still ongoing to evaluate the safety, tolerability as well as to define initial efficacy signal. We are also very happy to report that this program also has been filed for U.S. R&D. The R&D was cleared on June 1 this year. Next slide, just introduce our U.S. R&D study design. We are targeting the cloud positive patients based on mini [indiscernible] chemistry assets. The [indiscernible] population includes histological and [indiscernible] confirmed unresectable, locally advanced or metastatic adenocarcinoma of gastric and pancreatic among other cancer indication. We have 2 different parts in the Phase I design. Part A focused on gastric, GEJ and EC cancer patients at initial dose escalation phase to determine the tolerable dose. And then Part B focused expansion and expand patient indications, disease indication to include pancreatic patients as well. The second update I want to provide here is our program targeting GPC3. Again, this is autos CAR-T therapy product. GPC3 is oncofetal protein, which is highly expressed in tumor indication, including HCC and non-small cell lung cancer. We identified internal binders to the GPC3 with high affinity and specificity. Further, this product incorporates the set receptor armor, which convert immunosuppression into immune activity signal. Currently, this study -- these products and first-in-human clinical evaluation through IoT study in China. Again, we target GPC3 positive patients based on histochemistry assay. Those are adult patients with advanced HCC. Those patients are already progressed or intolerant after previous standard systemic therapy. The first patient was dosed in June this year, and currently, the RIT study is ongoing. Last program, which were introduced last year, we will provide an update in autologous CAR-T program targeting DLL3 for small cell lung cancer. DLL3 is a promising target due to its high expression in small cell lung cancer as well as in other neuroendocrine tumors. Its expansion in normal tissue is minimum or the not detectable. Small cell lung cancer is a disease with very limited treatment options. Very aggressive disease with very high unmet medical need. We use a tandem binder discovered through internal efforts and also coupled with unique armor mechanism, a dominant negative armor, which block the immune suppressant, signaling to enhance the immune cell activation position as well as to promote the invitation of immune cells in the tumor micro environment. Currently, these programs and IND-enabling study, and we plan to find U.S. R&D by Q4 this year. So those are a quick update on the 3 program we introduced last year. For solid tumor, we are very happy to introduce another program at today's update. This is [indiscernible]. This is autologous CAR-T program targeting GCC for gastrointestinal cancers. GCC is highly expressed in various gastric intestinal malignancy. And this target itself is also weakly expressed in normal intestinal epithelial cell by expansion is restricted to the luminal membrane side, and, therefore, provide mechanism to avoid the systemic immune toxicity against normal tissue. The binder itself is internally discovered. We also incorporate the armor design and have generated a comprehensive preclinical characterization data package for cell product. Currently, this product is in preparation for the first in-human study. So let's look at the expression in normal tissue first because safety is always our first priority. GCC, as you can see from this slide, the expansion pattern analyzed by the messenger RNA expression level, you can see that it's only restricted to small intensities and [indiscernible]. Looking at the exact location of expression in normal tissue. It is expressed in the epicedial cells, but only restricted to the nominal side. Happy to read a report in the digital a few years ago. And in that particular study, a CAR-T product targeting GCC was characterized as this particular CCC binder in that study cross react with mouse GCC. In that particular study, the CAR-T generated robust antitumor activity, but does not generate T cell immediate toxicity, indicating a safety -- a potential safety profile for this particular mechanism targeting GCC. Expansion in tumor is highest in various GI cancers, for example, in colon cancer and in gastric cancer. And those are indications it has large patient population and high medical [indiscernible] needs. In terms of our product design, our autologous CAR-T design using internal discovered binder with high affinity and specificity, coupled with [indiscernible], which function to convert immunosuppressive signal into immune activating signal. I will share some of our preclinical capitalization on this product. First, looking at the binder, we have high affinity binder at a nanomolar affinity. Importantly, we did an extensive assessment of binding specificity across 6,000 membrane protein analyzed. Our binder only recognizes GCC as you can see from the bottom left panel. In terms of cytotoxicity against the tumor servers normal cell which is used on the right side panel, our CAR-T product can effectively kill the tumor cell, but with minimum or low activity towards the normal nontransformed column [indiscernible] cells. We further characterized in the in-vivo pharmacology study taking 1 of the publicly released CAR in targeting the same target as a benchmark. We titrate on the dose such that our CAR still can generate durable and effective antitumor activity, leading to complete tumor remission, whereas at this particular dose, a benchmark design does not have any activity. Just to note, with this particular calculation, it is a CAR without the armor already providing this level of strong efficacy the PK profile in-vivo is consistent with the efficacy data. Next, we want to assess the benefit of adding armor mechanism. So in this particular pharmacology study, we have armored CAR versus armored CAR. 2 products have had comparison. We further titrated the dose even at the 0.1 million CAR-T cells, single infusion. Our armored product can lead to complete the tumor regression in a durable fashion, whereas an armored one can only generate the partial tumor growth inhibition, point to the benefit of this unique type of armor mechanism. To drive the antitumor activity, as you can appreciate from the right side panel, also enhance the exposure of the cell product. Just to summarize this particular product, [indiscernible], this is our autologous CAR-T product, the type GCC for gastrointestinal tumor indications. We use internally discovered and characterized the binders with high affinity specificity. Specificity is [indiscernible] across a large panel of membrane protein array. We couple this CAR design with a switch receptor or mechanism, and currently this program is in first-in-human study. So I will wrap up the introduction or the presentation on the solid tumor programs and switch gear and focus on the allogeneic platform. Here, I will introduce 2 different programs or platforms we have been developed in the past several years. The first is [indiscernible] program platform, and then second is [indiscernible] platform. Let's focus on the CAR NK for a minute. So as we all appreciate, NK cell represents [indiscernible] immune cell, experiencing various activity and inhibitor receptor. From the functional perspective, those NK activity receptor molecule can recognize various stress-related signal abundantly expressed in tumor cells. And therefore, NK cell represented a mechanism, which can kill the tumor cell in a very fast time scale given it's innate in nature, as well as they can provide a serious cytotoxicity against the tumor cell. Magnificently, it has multiple mechanism of cytotoxicity, CAR-dependent, CAR independent, which actually is very important for cancer indication because our targeted is generality is one of the big challenge in oncology, and HAVING car dependent as well as independent mechanism, would allow us to address the target [indiscernible] issue. I'd also have antibody mediated, the ADCC activity can secrete cytokine to communicate to the housing immune system to further augment the antitumor activity. So those unique attributes of NK make it ideal for allogeneic cell therapy approach. But it comes with its own challenge. And this slide shows some of those challenges. For example, short resistance, multiple dosing requirements, low transduction efficiency, difficult to maintain activity and cry preservation conditions. And lastly, but also equally, challenging is the average rejection issue when we try to develop allogeneic product. When we try to develop our internal NK allogeneic platform, those are the challenges we focus on, and I'm happy to report that with our current platform, we have been able to demonstrate the long-term antitumor activity at a very low dose, even single dose using our unique armor mechanism. And those are the preclinical data. And those programs are advancing into first-in-human study. We are very much looking forward to clinical response. From the manufacturing process, we engineer a very unique CMC process, which provides a robust transduction efficiency. We also think we optimize the crio preservation protocols to maintain the viability and functionality of CAR NK product. Further, we are engineering the anti host versus graft mechanism into our product. with our own IP positions, and this would help to enhance the persistence and efficacy of our product. Let's spend a minute to talk about the product attributes coming from our unique CMC manufacturing process. So in terms of purity, we routinely get the NK purity above 95% and CAR positivity of above 60%. Under our CMC manufacturing process, we can generate a robust NK expansion up to a few thousand fold. And those products has a very strong antitumor activity characterized in-vitro as well as in-vivo using preclinical system. Functional activity and pre-acquired preserve preservation is a big challenge for the entire field. We have a unique formulation protocol to address this issue. You can see that through the in-vitro and in-vivo capitalization. Our cryo preserved product and maintain the activity. So this slide just summarizes some of the key attributes of our product coming from the NK platform. On the CMC side, we have streamlined efficient manufacturing process. We can generate a few hundred doses per manufacturing process, assuming a flat dose of 3 million cells per dose. In terms of product efficacy and persistence, we have potent a nonterm antitumor efficacy, which we'll share in a subsequent slide, characterized by in-vivo pharmacology study preclinically. Design-wise, we tailor a unique immune signaling mechanism for the NK to design the CAR construct. On the binder side, we leveraged the learning from [indiscernible] cell to use the biparatopic or bispecific CAR design. HCC is another key component which we have been engineering and optimizing in the past several years. Now we have IP-protected strategy in this particular position for this particular platform. Even from pharmacology at relatively low dose, for example, at 1.5 million single dose in this particular in-vivo study, it generates complete tumor remission in a durable fashion. Looking at the PK, it's a very happy surprise to us. You can see that a single dose of allogeneic NK product, generally the PK exposure up to 60 days. And on the safety side, analyzing and with body weight, we do not see body weight loss over this entire treatment time scale. We can even further load those 2.5 million cells against a single dose leading to complete tumor remission and in a durable fashion. Similar to the other study, very robust PK exposition. We can even go a step further in this particular pharmacology study. Upon a single dose leading to complete tumor remission, we can challenge those completely remitted tumor with the same -- second inoculation of the same tumor, but without any additional dose of NK cell. You can see that with this second inoculation, 3 out of our 4 challenged animals remain the complete tumor remission without any additional dose, suggesting indicating the potency and activity for our CAR NK product. [indiscernible] rejection is another major challenge with the current NK therapy. That's probably one of the reason why the durability of clinical efficacy currently is, to a large extent, limited. For NK cells and there's 2 different mechanisms, which impact the rejection issue. First, graphite NK cell, expressed HLA ale, which can be recognized by host T cell to trigger [indiscernible] cell-mediated a rejection. This can be addressed through blockage for expression of HERA. So what we utilized in our product is, through knockdown of B2M, which block the surface expression HLA, which generated a secondary issue that is HLA expression on the cell surface, send an inhibitory signal to host NK cell, blocking the host NK cell media activity. By knockdown of B2M, you lost this inhibitor sign mechanism. So to address the whole NK allogeneic rejection in our cell product, we engineer knockdown of CD38. At the same time, with the clinical protocol with dose anti-CD38 monoclonal antibody, which can deplete the host NK cell without impact on the [indiscernible] NK product due to the knockdown of CD38 in our product. As you can see from the right bottom panel, if [indiscernible] is integrated with allogeneic NK product, initially, there's some level of NK expansions in the blue curve, light blue curve. But over time, the graph NK cell number reduce. By incorporating the CD38 knockdown in our NK product at the same time with the addition of daratuzumab, which depleted the NK cell from the PBMC, it extended the expansion phase of the graphic NK cell. So with this particular strategy, we can avoid the recognition of allogeneic NK cell by [indiscernible] and T cell. From a CMC manufacturing process, our engineering process has advantage in the sense -- in the form of -- it's a single vector single transduction, which can introduce car module, as well as introduce 2 different knockdown, and therefore, leading to a robust manufacturing process. Just to summarize our CAR NK platform, we have a unique armor mechanism which augmented the NK activity such that we can achieve a completed tumor remission at very low dose. At the same time, achieve a very extensive pronounced PK exposure in pre-clinical model up to 60 days. There's no obvious body weight loss based on the preclinical animal study. NK cells itself, at least in our platform, have robust expansion capacity, both in-vitro and in-vivo, which could offset some of the all rejection issue. At the same time, we will engineer a unique anti HBG mechanism to further address rejection challenge and hopefully enhance the persistence of our NK product. We developed a unique CMC manufacturing process with the product characterized with high-value transduction efficiency and high NK purage. This mantra manufacturing process also enhanced the metabolic fitness of NK product with lower exhaustive phenotype, leading to robust PK exposure. Single manufacturer can generate hundreds of those and optimize the cryo preservation protocols, maintain the NK cell viability and functionality. Currently, our lead program coming from this platform is undergoing IT study. And we are very much looking forward to see the data and hopefully share update at next year's R&D presentation. Lastly, I want to focus on the CAR gamma-delta generic platform. And this is a very exciting platform because of a unique biological nature of Gamma [indiscernible] as well as our unique design of this particular platform. Gamma [indiscernible] data represents a bridge between innate and adaptive immune response. It expressed both T cells, as well as NK cell receptor, and therefore, can facilitate both adaptive, as well as innate antitumor activity. This mechanism is particularly important to address the tumor target [indiscernible] as I already introduced in the NK platform. That's true also here. Further, the Gamma [indiscernible] immune cell has intrinsic ability to inflate, both into blood tumors, as well as solid tumor microenvironment. That's also very important for cell product activity. Lastly, but not least, large clinical correlation study, translational study, over thousands of tumor samples indicate that the presence of gamma [indiscernible] in the tumor microenvironment has the strongest correlation with the improved overall prognosis survival and the PFS. Among all the immune cell analyzed in that study, [indiscernible] has the best correlation, point to potential advantage of developing the allogeneic [indiscernible] product. From a safety perspective, it is also relatively simple to engineering because [indiscernible] does not have intrinsic GVHD risk. Manufacture wise, it can easily expand from donor-derived cell population. And it also has -- through our internal engineering and development, we have a robust GMP compliant manufacturing process. But this particular [indiscernible] also comes with its unique challenges as well. For example, [indiscernible] does not have a cytokine secretion to augment its own preference activation. And lastly, the second challenge is the potential annual rejection issue. So those are the 2 main areas we focus on our engineering effort. This slide introduces one of the internal platform. Currently, we are developing for the gamma data. It takes advantage or take the advantage of synergy between adaptive and innate immune signaling given that [indiscernible] is a hybrid of innate as well as adaptive immune cell lineage. So on the left side, it's a traditional CAR design, leading to activation of adaptive immunity and antitumor cytotoxicity. On the right side, we couple in immune activation with the tumor cell engagement, such that binding to a tumor cell energy lead to activation of innate immune intercession mechanism, driving the cytokine secretion, which can feed back and the function as a target manner to drive [indiscernible] expansion. The level of cytokine secretion through this engineer is actually below what commonly found in adaptive for immune cell, signing mechanisms such as [indiscernible]. And this is -- we will share some of the pre-clinical data on that topic. Let's focus on the manufacturing process for a minute, because this is an important issue for any cell product, especially when we enter or actually began to engineering a new cell image. Here, Legend has a tremendous advantage to leverage our cumulative learning from alpha-beta T production process. Over the past year, we have developed GMP-compliant manufacturing process, which is feeder-free, serum-free, fully enclosed and semi-automated. This manufacturing process offer consistency and stability. Single manufacturing process can generate hundreds and maybe up to 1,000 dose, assuming a flat dose of 100 million cells per dose. The manufacturer is very efficient. It can be accompanied in the time scale of 10 to 15 days. The cell product has a heavy enrichment in the memory phenotype with low expression of exhaustion mark. So expansion process illustrated in this slide, we can a single application and manufacturing process we can amplify the expense are up to a few thousand fold. The end product is heavily enriched in the central memory phenotype is characterizing [indiscernible] analysis. When we analyze the expression marker, it has a relatively low level of expansion use here with PD-1 and the TIGIT expression. I will introduce 1 product, a leading product utilized in this particular platform, LB2103. This is allogeneic product targeting multiple myeloma using the BCMA as a target. We have our traditional CAR-T design, recognizing BCMA with 1 unique binder and then an innate armor, coupled with a second binder, different binder, but against the same target BCMA target. I will introduce -- share some of the preclinical capitalization of this product. Just an update, currently, in term of clinical development state, currently, this product is an investigator-initiated study. So cytokine is important bets. And we know that one of the reasons why Alpha-Beta T are effective because it's hard dependent recognition, as well as cytokine secretion profile. But cytokine also come with a liability, which is potential systemic toxicity leading to cytokine release syndrome. We did a hyper-care comparison for silicon expression profile. From the [indiscernible] versus [indiscernible]. Let's focus on the [indiscernible] first, as you should here with the blue and the red bar. Those 2 red represent armored versus armories, looking at pro inflammation cytokines, such as interferon gamma and TNF alpha. Both form secrete those cytokines, and addition for armor itself does not further increase the cytokine secretion. When we did a head-to-head comparison with Alpha-Beta. You can see that, in general, [indiscernible] has lower sales situation compared to Alpha-Beta T, which is shaded blue bar. This characterizing point to a potential benefit of [indiscernible] platform, lower cytokine secretion in terms of pro information response could lead to a better safety profile. Even though the cytokine secretion is lower than Alpha-Beta T, if you focus on the right panel, looking at the cytotoxicity, [indiscernible] actually has more robust antitumor cytotoxicity point to a good balance between antitumor activity versus a potential safety profile. Antitumor activity is further catalyzed in in-vitro and in-vivo pharmacology models. Again, here, we compare armored and unarmored construct. Looking at in-vitro antitumor activity, upon repeated tumor incubation and repeat tumor kidney, [indiscernible] failed to cure tumors after 6 or 7 months, and that's the blue line and consistent with lack of [indiscernible] T cell expansion after 6 months. Whereas with our innate armor mechanism, the antitumor cytotoxicity is much more robust, extending to 9 or 10 round of repeated tumor incubation. And that's also very nicely [indiscernible] with [indiscernible] T cell Expansion in-vitro. This in-vitro finding is nicely translated into the in-vivo antitumor activity. An armored [indiscernible] only provide partial antitumor activity, which is not durable, whereas with armor version, you can see that we see complete tumor regression in a durable fashion. This profile, pharmacology profile, is consistent with the in-vivo [indiscernible] T cell expansion, [indiscernible] need to a much more robust PK exposure. Allo rejection is another concern, and we have 2 ways to address that. First, we want to assess the potential liability of Allo rejection, and this is what is in this slide. In a mixed lymphocyte experiment where we take allogeneic [indiscernible] mixed with PBMC plus tumor, and then analyze the expansion of allogeneic gamma [indiscernible] expansion in this initial system, the experimental condition is highly biased towards other rejection since we have for access of PBMC over the [indiscernible] product. First, let's look at the intrinsic ability of gamma [indiscernible] to expand. Under our target set where [indiscernible] and PBMC come from [indiscernible], that's represented in the right most panel, you can see that with or without armor, Gamma can expand in this time up to 9 days. Then we take this analysis into allogeneic format as show in 2 left panels using the different donors. With our armor mechanism, we can see that even in this allergenic settings, with potential allo rejection liability, our product can expand probably at least to 60% to 70% of the level or cell can expand, suggesting that the robust -- intrinsic robust expansion capacity, and to some extent, a limited liability of allo rejection used in this particular platform. Furthermore, we have divided the internal HVG mechanism, which can incorporate into our product. So just to summarize, we have a unique [indiscernible] platform, taking advantage of the innate armor mechanism, with our own strong IP protection. This unique armor mechanism need to robust expansion of [indiscernible] T cell and potent antitumor activity. This antitumor activity come both in the flavor of CAR-dependent, target independent as well as car independent cytotoxicity. Safety-wise, [indiscernible] do not have the GVHD burden. -- and our unique armor mechanism also reduce the expression of secretion of pro-inflammation cytokines [indiscernible] from the [indiscernible] and potentially provide advantage, potentially advantage on the safety front. We have developed an internal CMC process, which is feeder-free, CM-free and very robust manufacturing process, which offer consistency and scalability and the armor mechanism also enhanced expansion and our CMC manufacturing process can lead to several thousand fold expansion, leading to a few hundred up to 1,000 dose per manufacturing process. The product has enriched the [indiscernible] memory phenotype and improved the cell fineness with lower-level expression of exhaustion. Currently, our lead program is in clinical study. And hopefully, we can provide a clinical update at next year's R&D implementation. Just to wrap up, our global R&D strategy and execution side on 4 different pillars. And those are our people, our most important asset. We have a global research and development teams in U.S., in China, in EU. Our program platform are driven by science, and we focus on global innovation, continue to maintain our leadership in the cell therapy space. Everything we do is for the patients. We want to develop, discover and develop a first-in-class, best-in-class cell therapy product with strong IP position so that we can continue to benefit the patients. Clinical development wise, we have a new program in both U.S. and in China. We focus on diverse disease in hem malignancy, as well as in solid tumor in the form of autologous and allogeneic platform, utilizing diverse technology platform of [indiscernible] so that we have the option to develop the best product using the optimum platform to drive our R&D process. So I will stop here, and we can entertain questions.

All right. We will now open the floor for questions. Please raise your hand to -- we'll bring a mic over to you and state your name and firm, please. And then for those attending virtually, you can use the chat feature to post your questions, I'll read them out loud.

My name is Kelly Shi from Jefferies. Thank you for great presentations from all. Firstly, I have 2 questions for CARTITUDE-4 trials. So what would be the estimated split of patients who has 1, 2 or 3 pair line therapy enrolled in C4 trial? Would it be more equally distributed or exclude to second line, third line, given that we hear doctors commented that they look at the selection criteria with more focus on how many prior therapies instead of prior lines. So therefore, 1 triple regimen could be considered equal to 2 therapies. And I have a follow-up.

Sure. So I can try to answer that. So in terms of -- maybe to start with line of therapy, so clinical trial defined line of therapy, right? So every clinical trial, including this one, will have conservative approach. So it's not prior number of therapies, its prior line of therapy. And then like, for example, all frontline induction transplant and consolidation and maintenance is 1 line, right? So that's how clinical trials usually define. Now in terms of split of patient population, obviously, I have no data from CARTITUDE-4, so we cannot really comment on that. There are other trials in myeloma with 1 to 3 prior lines, and usually, it's equally distributed from previous trials, which have been Phase IIIs, which are being conducted and reported, but we have to see what CARTITUDE-4 will be.

And also C-4 trial in control arm allows for 2 associate regimens, PVD and DPD. And I wonder if the subgroup analysis based on these 2 different regimen will be conducted to offer like a better understanding how CARVYKTI compared against each of the regimen. This also could like resonate Steve's point that [indiscernible] design different in terms of fire [explorer ] to DARZALEX.

So yes, sure. So that's very important data, of course, to look. And yes, we will plan to report on some groups by treatment comparison. And as you said, it's randomized study. So it will compare DPD to these patients with CAR-T and PVD versus CAR-T.

To Dr. Fang if I may. So I'm curious about when you mentioned that innate immunity activation arm, does it require cost in domain and will that be? And also for most of this CAR-T design, do you also follow the same design for [ BCMA ] CAR-T has a dual branding domain?

Yes. So probably twofold with your question, one is on the bind itself. We take a similar design, but in terms of binders itself, it's different for cilta-cel. And indeed the [indiscernible], it's 1 -- common innate in [indiscernible] exact MOA, we probably won't disclose that at the time.

Tenthoff from Piper Sandler. So I wanted to kind of just get at a high level the strategy for bringing clinical studies, both in China and then to the U.S. is sort of the plan to kind of get initial proof of concept in China and then file in other global -- with other global regulatory agencies to conduct studies. Maybe you can just flush that out a little bit more sort of the high-level strategy.

Sure. So maybe I can start and anyone can answer. Yes, that's correct. I think right now, our approach is to do proof of concept in China to generate some proof of concept while we are working on establishing IND package for FDA because, as you know, IND requirements with FDA, Europe or other health authorities require some additional in vitro or in vivo characterization. So it takes few months as was manufacturing package readiness. So I think that's the approach.

Yes, probably I can...

And Ying maybe you want to add?

Go ahead.

Yes, I can probably also briefly comment on that. I think I have access to IIT study is a tremendous benefit that allow us to efficiently generate the clinical proof of concept. Exact nature of how we approach this question probably it will be dependent on the nature of the platform and the product itself. Overall, we want to -- 2 major goals. One is speed, and we want to generate fast validation. And the second is we want to utilize resource efficiency and enhance the overall success rate. So for a new platform, a new product, if we do not have sufficient experience and the preclinical data is uncertain in terms of the transmission potential into clinic, then the IIT study becomes the most effective requires to reach the clinical proof of concept quickly. But for a product, which we have experienced and we have confidence in terms of its potential transformation then going after the R&D finding will be most efficient way. Which market to [indiscernible] will depend on the natural product, the management need and the standard of care landscape. And from there, we can decide which market will be most attractive for us to go after in terms of R&D study.

And then, Ted, this is Ying. I just want to add a couple of things. If you noticed the history of development for cilta-cel, we did complete a Phase I that enroll a total of 74 patients in China first. So in that case, we could actually come to U.S. in a relatively faster fashion because we go into a Phase Ib dose-confirming and then seamlessly into a Phase II pivotal, right? Same thing for the case of LB1908 for the gastric cancer program, we have accumulated some clinical data that was actually included in the IND filing with the FDA. And then later, we got the FDA clearance for IND. But for 1 problem maybe you have noticed DLL3 we have decided to go directly into IND in the U.S. for which we're planning for IND application by end of this year.

Yes. That's all really helpful and all very clear. A follow-up question, if I may. I'm impressed by the suite of tools and innovations that you guys are bringing to different cell therapies. And I'm wondering how you will ultimately prioritize different products. So for example, maybe adding an armor technology or cytokine to an earlier product like 1908 or something like that. I'm just using that as an example. But how do you kind of bring those technologies forward and/or even develop iterative products? And then I guess the last question, if I may. Now that you've partnered cilta-cel CARVYKTI with JnJ, are you likely to do similar partnerships for the other assets in the pipeline? Or now that the company is bigger and obviously has greater financial resources, is a plan really to take these assets further along yourselves?

So I probably can address the first question, and then Ying can address the partner and overall development strategy question. So we are excited about all those tools we generate. And those 2 have always been explored and characterized and the developed in the context of our program, the project. We do not play around with tools or development tools for the sake of generating tools. The one way to look at this issue is always from an endpoint and that's what we focus on, right? For specialty disease, specialty product, what do we need to do to make it work. And from there, think about what toolbox we need to generate. For example, liquid tumor versus a solid tumor different disease indication, different the tumor micro environment. And then immune versus tumor cell attributes that we have determined whether we need the cytokine, whether we need to switch receptor. So in the context of product development, we're happy to report that now we have this very large collection. Again, how to use those tools into -- in covering those tools into future products will be driven by the disease and by the product [ HBs ], we want to engineer. Again, with -- even with those predefined approach, we always get surprise given the lack of -- or gap in preclinical -- [indiscernible] translation. And therefore, as you point out that iterative for engineering and forward translation, backward translation, taking the learning from the clinical study, especially in the early phase of IIT study and then that translate the engineering would be an important process for us.

So Ted, regarding the partnership question, I can tell you that we will look into the indication and then the addressable market. In the case of cilta-cel CARVYKTI, I mean, obviously made tremendous sense for us to be partnered with a powerhouse in the field multiple myeloma because Janssen has not only got the expertise in GMP manufacturing and also the clinical development. They also are developing some of the biggest hematology drugs, including IMBRUVICA, DARZALEX, so it makes a lot of sense. Future indications, I think will, again, like has looked into the indication addressable market. If it's a large indication that will require thousands of patients in the clinical development globally. We most actually will enter into a partnership discussion. I mean, in fact, we are in many different discussions with the various partners for potential collaborations. Certainly, we also welcomed the opportunity to form partnerships with other bio companies, which can bring into complementing technologies that will advance our pipeline as well.

This is Harshita Polishetty from Barclays representing Gena. The first 2 questions, perhaps for Steve and Ying. Steve, you mentioned right now, approximately 40 sites are active. If I remember correctly, that was the target for 2022. So do you plan on adding additional sites this year? Or would the focus be more increasing capacity at each site? So that's the first question. And then second one is on high-level safety for CARVYKTI and also market opportunity. As you mentioned, the patient numbers that you disclosed for C4, C5 and C6. So Parkinson is as you've implemented patient management strategies, and of course, the incident has gone down to less than 0.5% but as you go into earlier lines, how do you the risk reward? So do you take this into consideration? I know you mentioned like patient fitness and tumor burden, but how should we think about the incidence risk for Parkinsonism and how does that change the market opportunity? And then I have a last question for Dr. Fang.

Sure. Why don't I take a crack at the allocation methods and then maybe you could pick a crack at Parkinson then. We'll talk what we're hearing in market as it relates to earlier lines and what how our docs are thinking. So the allocation question. So the question is around today, we have roughly 40 sites, not roughly, 40 sites that are site certified. And really, our site build-out is really largely predicated on manufacturing capacity full stop. So I mentioned earlier when I was chatting about these trials, the most important thing for us from an allocation perspective is ensuring that whatever we commit to in market to a site, we deliver on 100% of the time, full stop. There's been some, like you said, there's been some examples in the market where that hasn't happened. And quite frankly, I think it's damaging the class. So we want to ensure that for patients, most importantly, that whatever we're committing to, we're delivering on. So the question about will we do more it's our intention over time to get to 80. The magic number of 80, again, that's a flexible number is largely predicated on supply. So as I become more and more reassured on supply, I will make appropriate steps to expand the market. If supply source of ramp -- rapidly ramp, you'll see a commensurate increase. The one thing we'll just caution you, and I've said this in other presentations is, what happens -- what I've been seeing is, what happens a lot is people are getting kind of hang on a number, 80 sites, 40 sites, whatever the sites are. The important number to take a look at, it's not so much the aggregate number. The aggregate number, don't get me wrong, is important, especially in large patient populations. I need mass in the market to pull that volume through. What's really important for us, though, and especially in this initial indication is our sites today have more than enough patients to hit our targets, our financial and patient targets. So my point is that in the United States, in particular, it's highly top-heavy in terms of number of sites. You have small numbers of sites with extremely large patient volumes. So that's why we're being very judicious in how we ramp but we will be ramping, like I said, with an eye on the future in terms of this second indication where I need to get to 70 to 80, I think you get beyond 80, I'm going to get beyond 80 as well because that's going to help patients because it'll get access size that are closer to our patient volumes. Do you want to talk about some of the toxicity?

Sure. So yes, I guess, from a clinical perspective I have mentioned, right now we see 0.5%. So this remains occasional adverse events, and it has been seen not only for this program, but we're also in a label for approved CAR-T, second CAR-T, that is Parkinson. So totality from a clinician perspective, and we have a lot of discussion, of course, with myeloma physician, even remains occasional and it's Parkinson-like symptoms. So it's not Parkinsonism per se and patients are stable, not requiring intervention or requiring some steroid intervention for a short period of time. So from a practice perspective, benefit drug can give, this is oncology, right? So events like this are happening. And if it remains occasional, incidence is low and stable or manageable so it will not trickle that's a feedback from experts as well.

Maybe if I just...

So now you have the commercial.

Yes. No, it's an important question because we talked a lot -- I talked a lot of the docs about this at ASCO recently. One of the things -- and you're right, your safety hurdle is getting higher, the earlier you go in line, right? And so even with great data, rightfully so, that risk-benefit ratio is changing because these patients -- there's other modalities, let's say, sit in earlier line. We just talked about some of the data [ Peter ] shared on how well combinations are doing an earlier line of therapy. What you will say what we are modeling, and I think folks who filed a myeloma, I think, would agree to this, we're going to see a high-risk population actively adapt without question, right? You're going to see quick conversion across. It's in that standard risk to low-ish risk but you're right. You're going to see that will be more of a lagging adoption for us. And that's why it's so important for us in the near term to get as many reps on this product and demonstrate the safety of cilta-cel, even in a late line patient that is really, you would think very susceptible to some of these toxicities. So it's very important, obviously, that we launch successful. We will, we are. But I think we do have -- you're right, a greater hurdle as we get in earlier lines of treatment for sure. If you have 1 more question.

And then actually, I see that, maybe I'll add that. Although we have not disclosed all the safety details from the other ongoing CAR-T program, including CAR-T 2, 4 and 5. However, what I can tell you is that categorically speaking because we do have to report all the safety events to all the global regulators. I can tell you, if you go into earlier patient population, including patients enrolling CAR-T 2, 4 and 5, overall, we may see a similar incidence of CRS and neurotox. However, the severity of those CRS and the neurotox actually, it's much more tolerable than what we saw in CARTITUDE-1 in the pre -- heavily pretreated patients.